3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh

ABSTRACT

The invention is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 -R 6  are defined herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.

FIELD OF THE INVENTION

The present invention is directed to novel3-pyrimidinyl-4-yl-oxazolidin-2-one compounds, compositions containingthese compounds, the use of such compounds in the inhibition of mutantIDH proteins having a neomorphic activity and in the treatment ofdiseases or disorders associated with such mutant IDH proteinsincluding, but not limited to, cell-proliferation disorders, such ascancer.

BACKGROUND OF THE INVENTION

Isocitrate dehydrogenase (IDH) is a key family of enzymes found incellular metabolism. They are NADP⁺/NAD⁺ and metal dependentoxidoreductases of the enzyme class EC 1.1.1.42. The wild type proteinscatalyze the oxidative decarboxylation of isocitrate toalpha-ketoglutarate generating carbon dioxide and NADPH/NADH in theprocess. They are also known to convert oxalosuccinate intoalpha-ketoglutarate. Mutations in IDH1 (cytosolic) and IDH2(mitochondrial) have been identified in multiple cancer types including,but not limited to, glioma, glioblastoma multiforme, paraganglioma,supratentorial primordial neuroectodermal tumors, acute myeloid leukemia(AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma,cholangiocarcinoma, peripheral T-cell lymphoma, and melanoma. (See L.Deng et al., Trends Mol. Med., 2010, 16, 387; T. Shibata et al., Am. J.Pathol., 2011, 178(3), 1395; Gaal et al., J. Clin. Endocrinol. Metab.2010; Hayden et al., Cell Cycle, 2009; Balss et al., Acta Neuropathol.,2008). The mutations have been found at or near key residues in theactive site: G97D, R100, R132, H133Q, and A134D for IDH1, and R140 andR172 for IDH2. (See L. Deng et al., Nature, 2009, 462, 739; L. Sellneret al., Eur. J. Haematol., 2011, 85, 457).

These mutant forms of IDH are shown to have a neomorphic activity (alsoknown as a gain of function activity), reducing alpha-ketoglutarate to2-hydroxyglutarate (2-HG). (See P. S. Ward et al., Cancer Cell, 2010,17, 225) In general, production of 2-HG is enantiospecific, resulting ingeneration of the D-enantiomer (also known as R enantiomer or R-2-HG).Normal cells have low native levels of 2-HG, whereas cells harboringthese mutations in IDH1 or IDH2 show significantly elevated levels of2-HG. High levels of 2-HG have been detected in tumors harboring themutations. For example, high levels of 2-HG have been detected in theplasma of patients with mutant IDH containing AML. (See S. Gross et al.,J. Exp. Med., 2010, 207(2), 339). High levels of 2-HG are highlyassociated with tumorigenesis.

Mutant IDH2 is also associated with the rare neurometabolic disorderD-2-hydroxyglutaric aciduria type II (D-2-HGA type II). Germlinemutations were found at R140 in IDH2 in 15 pateints having D-2-HGA typeII. Patients having this disorder also have consistently increasedlevels of D-2-HG in their urine, plasma and cerebrospinal fluid. (SeeKranendijk, M. et al., Science, 2010, 330, 336). Finally, patients withOilier Disease and Mafucci Syndrome (two rare disorders that predisposeto cartilaginous tumors) have been shown to be somatically mosaic forIDH1 and 2 mutations and exhibit high levels of D-2-HG. (See Amary etal., Nature Genetics, 2011 and Pansuriya et al., Nature Genetics, 2011).

Thus, there is a need for small molecule inhibitors of mutant IDHproteins having a neomorphic activity for the treatment of diseases anddisorders associated with these proteins.

SUMMARY OF THE INVENTION

In one aspect, this invention provides for a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein R¹-R⁶ are definedherein.

In a second aspect, this invention provides for a pharmaceuticalcomposition comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier orexcipient.

In a third aspect, this invention provides for the use of a compound offormula (I), or a pharmaceutically acceptable salt thereof, as aninhibitor of a mutant IDH protein having a neomorphic activity such asreducing alpha-ketoglutarate to 2-hydroxyglutarate (2-HG neomorphicactivity). Suitably, this invention provides for the use of a compoundof formula (I), or a pharmaceutically acceptable salt thereof, as aninhibitor of mutant IDH1 having a neomorphic activity, such as 2-HGneomorphic activity, and/or mutant IDH2 having a neomorphic activity,such as 2-HG neomorphic activity. This invention further provides forthe use of a compound of formula (I), or a pharmaceutically acceptablesalt thereof, as an inhibitor of IDH1 having a mutation at residue 97,100 or 132, for example G97D, R100Q, R132H, R132C, R132S, R132G, R132L,and R132V; and/or an inhibitor of IDH2 having a mutation at residue 140or 172, for example R172K, R172M, R172S, R172G, and R172W.

In a fourth aspect, this invention provides for a method of treating adisease or disorder associated with a mutant IDH protein having aneomorphic activity comprising administration of an effective amount ofa compound according to formula (I), or a pharmaceutically acceptablesalt thereof, to a subject in need thereof. In one embodiment, thedisease or disorder is a cell proliferation disorder, such as cancer. Inanother embodiment, the cancer is brain cancer, such as glioma,glioblastoma multiforme, paraganglioma, and supratentorial primordialneuroectodermal tumors (pNET); leukemia, such as acute myeloid leukemia(AML), myelodysplastic syndrome, and chronic myelogenous leukemia (CML);skin cancer, including melanoma; prostate cancer; thyroid cancer; coloncancer; lung cancer; sarcoma, including central chondrosarcoma, centraland periosteal chondroma; and fibrosarcoma. In another embodiment thedisease or disorder is D-2-hydroxyglutaric aciduria.

In a fifth aspect the invention provides for a compound of formula (I),or a pharmaceutically acceptable salt thereof, in combination withanother therapeutic agent.

These and other aspects of the present invention are described furtherin the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a compound of formula (I)

A compound of formula (I)

wherein:R¹ and R² are each independently hydrogen, deuterium, halo, hydroxyl,NH₂, aryl, heteroaryl, or optionally substituted C₁₋₄ alkyl,

wherein said C₁₋₄ alkyl is optionally substituted with one to threesubstituents each independently selected from the group consisting of:halo, hydroxyl, and NH₂;

R^(3a) is hydrogen, deuterium, C₁₋₆ alkyl, phenyl, or benzyl andR^(3b) is hydrogen, deuterium, or C₁₋₆ alkyl; orR^(3a) and R^(3b) are joined together forming an optionally substituted3-7 membered cycloalkyl ring or an optionally substituted 4-7 memberedheterocyclic ring,

wherein said cycloalkyl and heterocyclic rings are each optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of: halo, hydroxyl, oxo, NH₂, and C₁₋₃ alkyl;

R^(4a) is hydrogen, C₁₋₆ alkyl, optionally substituted phenyl,optionally substituted benzyl, optionally substituted heteroaryl, ormethylene-dibenzene,

wherein said phenyl, benzyl, and heteroaryl rings are optionallysubstituted with one to three substituents each independently selectedfrom the group consisting of: halo, hydroxyl, cyano, nitro, C₁₋₄ alkoxy,C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl,5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy, —COOR^(b),—SO₂R^(b), —NHC(O)R^(b), and —NR^(b)R^(b) and

R^(4b) is hydrogen, deuterium, or C₁₋₃ alkyl; orR^(4a) and R^(4b) are joined together forming an optionally substituted3-7 membered cycloalkyl ring or an optionally substituted 4-7 memberedheterocyclic ring,

wherein said cycloalkyl and heterocyclic rings are optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of: halo, hydroxyl, oxo, NH₂, and C₁₋₃ alkyl,

provided that only one of R^(3a) and R^(3b) and R^(4a) and R^(4b) arejoined together forming a ring;

R^(5a) is hydrogen or deuterium;R^(5b) is hydrogen, deuterium, methyl, ethyl, CD₃, CF₃, CH₂F, or CHF₂andR⁶ is optionally substituted C₁₋₆ alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted heterocyclic,or optionally substituted C₃₋₁₀ cycloalkyl,

wherein said C₁₋₆ alkyl is optionally substituted with one substituentselected from the group consisting of hydroxyl, C₁₋₃ alkoxy and —OR^(a),

wherein said aryl, heteroaryl, heterocyclic and C₃₋₁₀ cycloalkyl areoptionally substituted with one to three substituents each independentlyselected from the group consisting of: halo; hydroxyl; cyano; nitro;C₁₋₄ alkoxy; C₁₋₃ haloalkyl; C₁₋₃ haloalkoxy; C₁₋₆ alkyl; C₃₋₆cycloalkyl optionally substituted with one to three substituents eachindependently selected from the group consisting of: hydroxyl, cyano,C₁₋₃ alkyl, C₁₋₃ alkoxy, and C₁₋₃ haloalkyl; phenyl optionallysubstituted with one to three substituents each independently selectedfrom the group consisting of: halo, hydroxyl, cyano, nitro, C₁₋₃ alkoxy,C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, 5-6 membered heterocyclic, phenoxy, —COOR^(b),—SO₂R^(b), —NHC(O)R^(b), and —NR^(b)R^(b); 5-6 membered heteroaryloptionally substituted with one to three substituents each independentlyselected from the group consisting of: halo, hydroxyl, cyano, C₁₋₃alkyl, C₁₋₃ alkoxy; 5-6 membered heterocyclic optionally substitutedwith one to three substituents each independently selected from thegroup consisting of: halo, hydroxyl, oxo, NH₂, and C₁₋₃ alkyl;—CH₂R^(a); —OR^(a); —C(O)R^(a); —NR^(a)R^(b); —COOR^(a); —SO₂R^(a);—SO₂R^(b); NHC(O)R^(a); —NHC(O)R^(b); —C(O)NR^(a)R^(b); —C(O)NHR^(b);and —SO₂NR^(b)R^(b); or

R^(5b) and R⁶ are joined together forming an optionally substituted C₃₋₇cycloalkyl group or an optionally substituted group of formula (a):

wherein n is 1, 2, or 3 and

said C₃₋₇ cycloalkyl and group of formula (a) are optionally substitutedwith one to three substituents each independently selected from thegroup consisting of: halo, hydroxyl, cyano, nitro, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, 5-6 membered heterocyclic, benzyloxy, —COOR^(b), —SO₂R^(b),—NHC(O)R^(b), and —NR^(b)R^(b);

each R^(a) is independently optionally substituted phenyl, optionallysubstituted heteroaryl, optionally substituted heterocyclic, oroptionally substituted C₃₋₇ cycloalkyl,

wherein said phenyl and heteroaryl are optionally substituted with oneto three substituents each independently selected from the groupconsisting of halo, hydroxyl, cyano, nitro, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,C₁₋₃ haloalkoxy, and C₁₋₃ alkyl,

wherein said heterocyclic is optionally substituted with one to threesubstituents each independently selected from the group consisting ofhalo, hydroxyl, oxo, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₁₋₄alkyl, C₃₋₅ cycloalkyl, —C(O)R^(b), and —NR^(b)R^(b); and

wherein said C₃₋₇ cycloalkyl is optionally substituted with one to threesubstituents each independently selected from the group consisting ofhalo, hydroxyl, oxo, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, andC₁₋₃ alkyl; and

each R^(b) is independently hydrogen or C₁₋₆ alkyl.

“Alkyl” refers to a monovalent saturated hydrocarbon chain having thespecified number of carbon atoms. For example, C₁₋₆ alkyl refers to analkyl group having from 1 to 6 carbon atoms. Alkyl groups may beoptionally substituted with one or more substituents as defined informula (I). Alkyl groups may be straight or branched. Representativebranched alkyl groups have one, two, or three branches. Examples ofalkyl groups include, but are not limited to, methyl, ethyl, propyl(n-propyl and isopropyl), butyl (n-butyl, isobutyl, sec-butyl, andt-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.

“Alkoxy” refers to any alkyl moiety attached through an oxygen bridge(i.e. a —O—C₁₋₃ alkyl group wherein C₁₋₃ alkyl is as defined herein).Examples of such groups include, but are not limited to, methoxy,ethoxy, and propoxy.

“Aryl” refers to a hydrocarbon ring system having an aromatic ring. Arylgroups are monocyclic ring systems or bicyclic ring systems. Monocyclicaryl ring refers to phenyl. Bicyclic aryl rings refer to naphthyl and torings wherein phenyl is fused to a C₅₋₇ cycloalkyl or C₅₋₇ cycloalkenylring as defined herein. Aryl groups may be optionally substituted withone or more substituents as defined in formula (I).

“Cycloalkyl” refers to a saturated hydrocarbon ring system having thespecified number of carbon atoms. Cycloalkyl groups are monocyclic orbicyclic ring systems. For example, C₅₋₁₀ cycloalkyl refers to acycloalkyl group having from 5 to 10 carbon atoms. Cycloalkyl groups maybe optionally substituted with one or more substituents as defined informula (I). Examples of cycloalkyl groups include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andadamantanyl.

“Cycloalkenyl” refers to an unsaturated hydrocarbon ring system havingthe specified number of carbon atoms and having a carbon-carbon doublebond within the ring. For example, C₅₋₇ cycloalkenyl refers to acycloalkenyl group having from 5 to 7 carbon atoms. In certainembodiments, cycloalkenyl groups have one carbon-carbon double bondwithin the ring. In other embodiments, cycloalkeneyl groups have morethan one carbon-carbon double bond within the ring. Cycloalkenyl ringsare not aromatic. Cycloalkenyl groups may be optionally substituted withone or more substituents as defined in formula (I).

“Halo” refers to the halogen radicals fluoro, chloro, bromo, and iodo.

“Haloalkyl” refers to an alkyl group wherein at least one hydrogen atomattached to a carbon atom within the alkyl group is replaced with halo.The number of halo substituents includes, but is not limited to, 1, 2,3, 4, 5, or 6 substituents. Haloalkyl includes, but is not limited to,monofluoromethyl, difluoroethyl, and trifluoromethyl.

“Haloalkoxy” refers to a haloalkyl moiety attached through an oxygenbridge (i.e. a —O—C₁₋₃ haloalkyl group wherein C₁₋₃ haloalkyl is asdefined herein). An example of a haloalkoxy group is trifluoromethoxy.

“Heteroaryl” refers to an aromatic ring system containing from 1 to 5heteroatoms. Heteroaryl groups containing more than one heteroatom maycontain different heteroatoms. Heteroaryl groups may be optionallysubstituted with one or more substituents as defined in formula (I).Heteroaryl groups are monocyclic ring systems or are fused bicyclic ringsystems. Monocyclic heteroaryl rings have from 5 to 6 ring atoms.Bicyclic heteroaryl rings have from 8 to 10 member atoms. Bicyclicheteroaryl rings include those ring systems wherein a heteroaryl ring isfused to a phenyl ring. Heteroaryl includes, but is not limited to,pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl(including 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl), thiazolyl,isothiazolyl, thiadiazolyl, furanyl, furanzanyl, thienyl, triazolyl,pyridinyl (including 2-, 3-, and 4-pyridinyl), pyrimidinyl, pyridazinyl,pyrazinyl, trazinyl, tetrazinyl, tetrzolyl, indonyl, isoindolyl,indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl,quinoxalinyl, quinazolinyl, benzimidazolyl, benzopyranyl, benzopyranyl,benzoxazolyl, benzoisoxazolyl, benzofuranyl, benzothiazolyl,benzothienyl, naphthyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,tetrazolo[1,5-a]pyridinyl, imidazo[2,1-b][1,3,4]thiadiazolyl and thelike.

“Heteroatom” refers to a nitrogen, oxygen, or sulfur atom.

“Heterocyclic” refers to a 3 to 11 membered saturated or unsaturatedmonocyclic or bicyclic ring containing from 1 to 4 heteroatoms.Heterocyclic ring systems are not aromatic. Heterocyclic groupscontaining more than one heteroatom may contain different heteroatoms.Heterocyclic includes ring systems wherein a sulfur atom is oxidized toform SO or SO₂. Heterocyclic groups may be optionally substituted withone or more substituents as defined in formula (I). Heterocyclic groupsare monocyclic, spiro, or fused or bridged bicyclic ring systems.Monocyclic heterocyclic rings have 3 to 7 ring atoms. Examples ofmonocyclic heterocyclic groups include oxtanyl, tetrahydrofuranyl,dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl,piperidinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl,pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl,dithiolanyl, 1,3-dioxanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl,tetrahydro-thiopyran1,1-dioxide, 1,4-diazepanyl, and the like. Fusedheterocyclic ring systems have from 8 to 11 ring atoms and includegroups wherein a heterocyclic ring is fused to a phenyl ring, aheteroaryl ring or another heterocyclic ring. Examples of fusedheterocyclic rings include 2,3-dihydrobenzo[b][1,4]dioxinyl,octahydro-pyrrolo[1,2-a]pyrazinyl, octahydro-pyrido[1,2-a]pyrazinyl,octahydro-pyrrolo[3,4-c]pyrrolyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazinyl and the like. Examples ofbridged heterocyclic groups include 3,8-diaza-bicyclo[3.2.1]octanyl,3,8-diaza-bicyclo[4.2.0]octanyl and the like. Examples of spiroheterocyclic groups include 4,7-diaza-spiro[2.5]octanyl and the like.

“4-7 membered heterocyclic” refers to a heterocyclic group as definedabove, having from 4 to 7 ring atoms and containing from 1 to 4heteroatoms.

“5-6 membered heterocylic” refers to a heterocyclic group as definedabove, having 5 or 6 ring atoms and containing from 1 to 4 heteroatoms.

“Optionally substituted” indicates that a group, such as an alkyl,cycloalkyl, heteroaryl, heterocyclic, phenyl, and benzyl may beunsubstituted or the group may be substituted with one or moresubstituents as defined in formula (I).

“Oxo” refers to a C═O group.

“Pharmaceutically acceptable” means a compound which is suitable forpharmaceutical use. Salts and solvates (e.g. hydrates and hydrates ofsalts) of compounds of the invention which are suitable for use inmedicine are those where in the counterion or associated solvent ispharmaceutically acceptable. However, salts and solvates havingnon-pharmaceutically acceptable counterions or associated solvents arewithin the scope of the present invention, for example, for use asintermediates in the preparation of other compounds of the invention andtheir pharmaceutically acceptable salts and solvates.

“Substituted” in reference to a group such as alkyl, phenyl, benzyl,heteroaryl, and heterocyclic, indicates that one or more hydrogen atomsattached to an atom within the group is replaced with a substituentselected from the group of defined substituents. It should be understoodthat the term “substituted” includes the implicit provision that suchsubstitution be in accordance with permitted valence of the substitutedatom and the substituent, and that the substitution results in a stablecompound (i.e. one that does not spontaneously undergo transformation,for example, by hydrolysis, rearrangement, cyclization, or eliminationand that is sufficiently robust to survive isolation from a reactionmixture). When it is stated that a group may contain one or moresubstituents, one or more (as appropriate) atoms within the group may besubstituted. In addition, a single atom within the group may besubstituted with more than one substituent as long as such substitutionis accordance with the permitted valence of the atom. Suitablesubstituents are defined for each substituted or optionally substitutedgroup.

The skilled artisan will appreciate that salts, includingpharmaceutically acceptable salts, of the compounds according to formula(I) may be prepared. These salts may be prepared in situ during thefinal isolation and purification of the compound, or by separatelyreacting the purified compound in its free acid or free base form with asuitable base or acid, respectively.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Solvates, including pharmaceutically acceptable solvates, of thecompounds of formula (I) may also be prepared. “Solvate” refers to acomplex of variable stoichiometry formed by a solute and solvent. Suchsolvents for the purpose of the invention may not interfere with thebiological activity of the solute. Examples of suitable solventsinclude, but are not limited to, water, MeOH, EtOH, and AcOH. Solvateswherein water is the solvent molecule are typically referred to ashydrates. Hydrates include compositions containing stoichiometricamounts of water, as well as compositions containing variable amounts ofwater.

The compounds of formula (I), including salts and solvates thereof, mayexist in crystalline forms, non-crystalline forms, or mixtures thereof.The compound or salt or solvate thereof may also exhibit polymorphism,i.e. the capacity of occurring in different crystalline forms. Thesedifferent crystalline forms are typically known as “polymorphs”.Polymorphs have the same chemical composition but differ in packing,geometrical arrangement, and other descriptive properties of crystallinesolid state. Polymorphs, therefore, may have different physicalproperties such as shape, density, hardness, deformability, stability,and dissolution properties. Polymorphs typically exhibit differentmelting points, IR spectra, and X-ray powder diffraction patterns, allof which may be used for identification. One of ordinary skill in theart will appreciate that different polymorphs may be produced, forexample, by changing or adjusting the conditions used incrystallizing/recrystallizing a compound of formula (I).

The invention also includes various isomers of the compounds of formula(I). “Isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereosiomers). Withregard to stereoisomers, the compounds of formula (I) may have one ormore asymmetric carbon atom and may occur as racemates, racemic mixturesand as individual enantiomers or diastereomers. All such isomeric formsare included within the present invention, including mixtures thereof.If the compound contains a double bond, the substituent may be in the Eor Z configuration. If the compound contains a disubstituted cycloalkyl,the cycloalkyl substituent may have a cis- or trans-configuration. Alltautomeric forms are also intended to be included.

Any asymmetric atom (e.g., carbon or the like) of a compound of formula(I) can be present in racemic or enantiomerically enriched, for examplethe (R)-, (S)- or (R,S)-configuration. In certain embodiments, eachasymmetric atom has at least 50% enantiomeric excess, at least 60%enantiomeric excess, at least 70% enantiomeric excess, at least 80%enantiomeric excess, at least 90% enantiomeric excess, at least 95%enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or(S)-configuration. Substituents at atoms with unsaturated double bondsmay, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of formula (I) can be in the formof one of the possible isomers, rotamers, atropisomers, tautomers ormixtures thereof, for example, as substantially pure geometric (cis ortrans) isomers, diastereomers, optical isomers (antipodes), racemates ormixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

The invention includes unlabeled forms as well as isotopically labeledforms of compounds of formula (I). Isotopically labeled compounds havestructures depicted by the formulas given herein except that one or moreatoms are replaced by an atom having a selected atomic mass or massnumber. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵I respectively. The invention includesvarious isotopically labeled compounds as defined herein, for examplethose into which radioactive isotopes, such as ³H and ¹⁴C, or those intowhich non-radioactive isotopes, such as ²H and ¹³C are present. Suchisotopically labelled compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F or labeled compound may be particularlydesirable for PET or SPECT studies. Isotopically-labeled compounds offormula (I) can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples and Preparations using an appropriateisotopically-labeled reagents in place of the non-labeled reagentpreviously employed.

Furthermore, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Representative Embodiments

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide for further embodiments.

One embodiment of the present invention is a compound according toformula (I) wherein:

each R¹ and R² is independently hydrogen, deuterium, halo, hydroxyl,NH₂, aryl, heteroaryl, or optionally substituted C₁₋₄ alkyl,

wherein said C₁₋₄ alkyl is optionally substituted with one to threesubstituents each independently selected from the group consisting of:halo, hydroxyl, and NH₂;

R^(3a) is hydrogen, deuterium, C₁₋₆ alkyl, phenyl, or benzyl andR^(3b) is hydrogen, deuterium, or C₁₋₆ alkyl; orR^(3a) and R^(3b) are joined together forming an optionally substituted3-7 membered cycloalkyl ring or an optionally substituted 4-7 memberedheterocyclic ring,

wherein said cycloalkyl and heterocyclic rings are optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of: halo, hydroxyl, oxo, NH₂, and C₁₋₃ alkyl;

R^(4a) is hydrogen, C₁₋₆ alkyl, optionally substituted phenyl,optionally substituted benzyl, optionally substituted heteroaryl, ormethylene-dibenzene,

wherein said phenyl, benzyl, and heteroaryl rings are optionallysubstituted with one to three substituents each independently selectedfrom the group consisting of: halo, hydroxyl, cyano, nitro, C₁₋₃ alkoxy,C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, 5-6 membered heterocyclic, phenoxy, COOR^(b),SO₂R^(b), NHC(O)R^(b), and NR^(b)R^(b) and

R^(4b) is hydrogen, deuterium, or C₁₋₃ alkyl; orR^(4a) and R^(4b) are joined together forming an optionally substituted3-7 membered cycloalkyl ring or an optionally substituted 4-7 memberedheterocyclic ring,

wherein said cycloalkyl and heterocyclic rings are optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of: halo, hydroxyl, oxo, NH₂, and C₁₋₃ alkyl,

provided that only one of R^(3a) and R^(3b) and R^(4a) and R^(4b) arejoined together forming a ring;

R^(5a) is hydrogen or deuterium;R^(5b) is hydrogen, deuterium, methyl, ethyl, CD₃, CF₃, CH₂F, or CHF₂andR⁶ is optionally substituted C₁₋₆ alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted heterocyclic,or optionally substituted C₅₋₁₀ cycloalkyl,

wherein said C₁₋₆ alkyl is optionally substituted with one substituentselected from the group consisting of hydroxyl, C₁₋₃ alkoxy and —OR^(a);

wherein said aryl, heteroaryl, heterocyclic and C₅₋₁₀ cycloalkyl areoptionally substituted with one to three substituents each independentlyselected from the group consisting of: halo; hydroxyl; cyano; nitro;C₁₋₃ alkoxy; C₁₋₃ haloalkyl; C₁₋₃ haloalkoxy; C₁₋₆ alkyl; C₃₋₆cycloalkyl; phenyl optionally substituted with one to three substituentseach independently selected from the group consisting of: halo,hydroxyl, cyano, nitro, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 5-6 memberedheterocyclic, phenoxy, COOR^(b), SO₂R^(b), NHC(O)R^(b), and NR^(b)R^(b);5-6 membered heteroaryl; 5-6 membered heterocyclic optionallysubstituted with one to three substituents each independently selectedfrom the group consisting of: halo, hydroxyl, oxo, NH₂, and C₁₋₃ alkyl;—CH₂R^(a); —OR^(a); —C(O)R^(a); —NR^(a)R^(b); —COOR^(a); —SO₂R^(a);NHC(O)R^(a); and —SO₂NR^(b)R^(b); or

R^(5b) and R⁶ are joined together forming an optionally substituted C₃₋₇cycloalkyl group or an optionally substituted group of formula (a):

wherein n is 1, 2, or 3 and

said C₃₋₇ cycloalkyl and group of formula (a) are optionally substitutedwith one to three substituents each independently selected from thegroup consisting of: halo, hydroxyl, cyano, nitro, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, 5-6 membered heterocyclic, benzyloxy, COOR^(b), SO₂R^(b),NHC(O)R^(b), and NR^(b)R^(b);

each R^(a) is independently optionally substituted phenyl, optionallysubstituted heteroaryl, or optionally substituted 4-7 memberedheterocyclic,

wherein said phenyl and heteroaryl are optionally substituted with oneto three substituents each independently selected from the groupconsisting of halo, hydroxyl, cyano, nitro, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,C₁₋₃ haloalkoxy, and C₁₋₃ alkyl,

wherein said 4-7 membered heterocyclic is optionally substituted withone to three substituents each independently selected from the groupconsisting of halo, hydroxyl, oxo, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃haloalkoxy, and C₁₋₃ alkyl; and

each R^(b) is independently hydrogen or C₁₋₆ alkyl.

In another embodiment of the present invention R¹ is hydrogen, halo, oroptionally substituted C₁₋₄ alkyl. Suitably R¹ is hydrogen, fluoro,chloro, or methyl. In another embodiment R¹ is hydrogen, fluoro orchloro. Suitably R¹ is hydrogen.

In another embodiment of the present invention R² is hydrogen, halo oroptionally substituted C₁₋₄ alkyl. Suitably R² is hydrogen, fluoro,chloro, or methyl. In another embodiment R² is hydrogen or fluoro. Inanother embodiment of the present invention R² is hydrogen.

In another embodiment of the present invention R¹ and R² are bothhydrogen.

In another embodiment of the present invention R^(3a) is hydrogen, C₁₋₆alkyl, or phenyl. Suitably R^(3a) is hydrogen, methyl, or phenyl.Suitably R^(3a) is hydrogen or methyl. Suitably R^(3a) is hydrogen.

In another embodiment of the present invention R^(3b) is hydrogen ormethyl. Suitably R^(3b) is hydrogen.

In another embodiment R^(3a) and R^(3b) are both hydrogen.

In another embodiment of the present invention R^(3a) and R^(3b) arejoined together forming oxetanyl or tetrahydro-2H-pyranyl.

Another embodiment of the present invention is a compound according toformula (II).

In another embodiment of the present invention R^(4a) is hydrogen, C₁₋₆alkyl, optionally substituted phenyl, optionally substituted benzyl,optionally substituted heteroaryl, or methylene-dibenzene,

wherein said phenyl, benzyl, and heteroaryl rings are optionallysubstituted with one to three substituents each independently selectedfrom the group consisting of: halo, hydroxyl, cyano, nitro, C₁₋₃ alkoxy,C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, 5-6 membered heterocyclic, phenoxy, —COOR^(b),—SO₂R^(b), —NHC(O)R^(b), and —NR^(b)R^(b).

In another embodiment of the present invention R^(4a) is hydrogen, C₁₋₄alkyl, optionally substituted phenyl, optionally substituted benzyl,optionally substituted heteroaryl, or methylene-dibenzene. SuitablyR^(4a) is hydrogen, C₁₋₄ alkyl, optionally substituted phenyl,optionally substituted benzyl, optionally substituted pyridinyl, ormethylene-dibenzene. More suitably R^(4a) is hydrogen, methyl,isopropyl, isobutyl, t-butyl, phenyl, 4-methoxyphenyl, 4-fluorophenyl,benzyl, or methylene-dibenzene. In another embodiment R^(4a) ishydrogen, methyl, ethyl, isopropyl, phenyl, 4-fluorophenyl,4-methoxyphenyl, biphenyl, benzyl, or pyridinyl. Suitably R^(4a) isisopropyl.

In another embodiment of the present invention R^(4b) is hydrogen ormethyl. Suitably R^(4b) is hydrogen.

In another embodiment R^(4a) is isopropyl and R^(4b) is methyl. Inanother embodiment R^(4a) is isopropyl and R^(4b) is hydrogen.

In another embodiment of the present invention R^(4a) and R^(4b) arejoined together forming cyclopentyl.

Another embodiment of the present invention is a compound according toformula (III).

In another embodiment of the present invention R^(5a) is hydrogen. Inanother embodiment R^(5a) is deuterium.

In another embodiment of the present invention R^(5b) is hydrogen,methyl, ethyl, or CF₃. Suitably R^(5b) is methyl.

In another embodiment of the present invention R⁶ is isopropyl,optionally substituted aryl, optionally substituted pyrazolyl,optionally substituted pyridinyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzo[b][1,4]dioxinyl, or optionally substituted C₅₋₁₀cycloalkyl. Suitably R⁶ is isopropyl, optionally substituted phenyl,optionally substituted naphthyl, pyrazolyl, pyridinyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or C₅₋₁₀cycloalkyl, wherein said phenyl and naphthyl are each optionallysubstituted with one to three substituents each independently selectedfrom the group consisting of: fluoro, chloro, bromo, hydroxy, cyano,methoxy, trifluoromethyl, methyl, t-butyl, phenyl, pyrrolyl,piperidinyl, 4-methylpiperazinyl, morpholinyl, phenoxy, and —SO₂NH₂.

In another embodiment of the present invention R⁶ is optionallysubstituted heteroaryl, optionally substituted heterocyclic oroptionally substituted C₅₋₁₀ cycloalkyl.

In another embodiment of the present invention R⁶ is methyl, C₅₋₁₀cycloalkyl, optionally substituted phenyl, optionally substitutedpyridinyl, optionally substituted pyrimidinyl, optionally substitutedpyridazinyl, optionally substituted pyrazinyl, optionally substitutedtriazolyl, optionally substituted pyrazolyl, optionally substitutedthiazolyl, optionally substituted 1,3,4-oxadiazolyl, optionallysubstituted 1,2,4-oxadiazolyl, optionally substituted isoxazolyl,thienyl, oxazolyl, quinolinyl, optionally substituted benzimidazolyl,benzthiazolyl, benzoxazolyl, tetrazolo[1,5-a]pyridinyl,imidazo[2,1-b][1,3,4]thiadiazolyl, optionally substituted piperidinyl,optionally substituted piperazinyl, tetrahydrofuranyl,tetrahydropyranyl, optionally substitutedtetrahydro-thiopyran1,1-dioxide, 1H-pyrrolo[2,3-b]pyridinyl,2,3-dihydro-benzo[1,4]dioxinyl,5,6,7,8-tetrahydro-[1,2,4]trazolo[4,3-a]pyrazinyl,4,5,6,7-tetrahydro-benzothiazolyl, or indolizinyl, wherein said phenyl,pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, pyrazolyl,thiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, isoxazolyl,benzimidazolyl, piperidinyl, piperazinyl, andtetrahydro-thiopyran1,1-dioxide are each optionally substituted with oneor two substituents as defined in formula (I). Suitably R⁶ is phenyloptionally substituted with one or two substituents. Suitably R⁶ isoptionally substituted 1,3,4-oxadiazolyl or 1,2,4-optionally substitutedoxadiazolyl. Suitably R⁶ is pyrimidinyl optionally substituted with onesubstituent.

In another embodiment R⁶ is optionally substituted with one or twosubstituents each independently selected from the group consisting of:halo; hydroxy; nitro; C₁₋₄ alkoxy; C₁₋₃ haloalkyl; C₁₋₃ haloalkoxy; C₁₋₆alkyl; C₃₋₆ cycloalkyl optionally substituted with one substituentselected from the group consisting of: cyano, C₁₋₃ alkyl, and C₁₋₃alkoxy; phenyl optionally substituted with one or two substituents eachindependently selected from the group consisting of: fluoro, chloro,methyl, cyano, and methoxy; and 5-6 membered heteroaryl (for example,imidazolyl, pyrazolyl, trazolyl, and pyridinyl) optionally substitutedwith one or two methyl groups.

In another embodiment R⁶ is substituted with one —CH₂R^(a), —C(O)R^(a),—NHC(O)R^(a), —NHC(O)R^(b), —C(O)NHR^(a), —C(O)NHR^(b), —OR^(a),—NR^(a)R^(b), —SO₂NR^(b)R^(b), —SO₂R^(a), or —SO₂R^(b) group. SuitablyR⁶ is substituted with one —CH₂R^(a), —C(O)R^(a), or —OR^(a) group.

In another embodiment R⁶ is phenyl substituted with one fluoro or chlorogroup and one —CH₂R^(a), —C(O)R^(a), or —C(O)NHR^(a) group wherein the—CH₂R^(a), —C(O)R^(a), or —C(O)NHR^(a) group is in the para position ofthe phenyl ring. Suitably R⁶ is phenyl substituted with one fluoro groupand one —CH₂R^(a), —C(O)R^(a), or —C(O)NHR^(a) group wherein the—CH₂R^(a), —C(O)R^(a), or —C(O)NHR^(a) group is in the para position ofthe phenyl ring. In another embodiment R⁶ is phenyl substituted with one—CH₂R^(a), —C(O)R^(a), or —C(O)NHR^(a) group in the para position. Inanother embodiment R⁶ is phenyl substituted by —CH₂R^(a) in the paraposition.

In another embodiment R^(a) is phenyl optionally substituted with one ortwo substituents each independently selected from the group consistingof fluoro, chloro and bromo.

In another embodiment R^(a) is an optionally substituted 5-6 memberedheteroaryl. Suitably R^(a) is optionally substituted pyridinyl oroptionally substituted pyrimidinyl. Suitably R^(a) is pyridinyl orpyrimidinyl optionally substituted with one trifluoromethyl.

In another embodiment R^(a) is C₅₋₇ cycloalkyl each of which isoptionally substituted with one or two substituents each independentlyselected from the group consisting of fluoro, hydroxy, methyl, and C₁₋₃haloalkoxy.

In another embodiment R^(a) is optionally substituted heterocyclic.Suitably R^(a) is piperidinyl, piperazinyl, morpholinyl,tetrahydropyranyl, tetrahydro-thiopyran1,1-dioxide, 1,4-diazepanyl,4,7-diaza-spiro[2.5]octanyl, 3,8-diaza-bicyclo[3.2.1]octanyl,3,8-diaza-bicyclo[4.2.0]octanyl, octahydro-pyrrolo[1,2-a]pyrazinyl,octahydro-pyrido[1,2-a]pyrazinyl, octahydro-pyrrolo[3,4-c]pyrrolyl, and5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazinyl each of which is optionallysubstituted with one to three substituents each independently selectedfrom the group consisting of: hydroxy, fluoro, amino, dimethylamino,C₁₋₃ haloalkoxy, C₁₋₃ alkyl, and C₃₋₅ cycloalkyl. Suitably R^(a) ispiperidinyl, piperazinyl, or morpholinyl each of which is optionallysubstituted with one to three substituents each independently selectedfrom the group consisting of: hydroxy, fluoro, amino, dimethylamino,C₁₋₃ haloalkoxy, C₁₋₃ alkyl, and C₃₋₅ cycloalkyl.

In another embodiment of the present invention R^(5b) and R⁶ are joinedtogether forming an optionally substituted C₃₋₇ cycloalkyl group or anoptionally substituted group of formula (a).

In another embodiment of the present invention each R^(b) isindependently hydrogen or methyl.

In another embodiment R¹ is hydrogen, R² is fluoro and R^(3a), R^(3b),R^(4a) and R^(4b) are each hydrogen.

Another embodiment of the present invention is a compound according toformula (IV).

Another embodiment of the present invention is a compound according toformula (V):

wherein R^(4a) is phenyl and R^(4b) is hydrogen.

Selected compounds of the present invention include:

-   (S)-4-isopropy-3-(2-(((S)-1-(4-(2-yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   N-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)phenyl)cyclohexanecarboxamide;-   (S)-3-(2-(((S)-1-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-4-isopropyl-3-(2-(((S)-1-(4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   2-fluoro-N-(4-hydroxy-4-methylcyclohexyl)-4-((S)-1-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)benzamide;-   (S)-3-(2-((S)-1-(4-((4-amino-4-methylpiperidin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-((S)-1-(4-((4-(dimethylamino)piperidin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-4-isopropyl-3-(2-((S)-1-(4-((4-methylpiperazin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;-   (S)-4-isopropyl-4-methyl-3-(2-((S)-1-(4-((4-methylpiperazin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;-   (S)-4-isopropyl-3-(2-((S)-1-(6-phenylpyridin-3-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;-   (S)-3-(2-((S)-1-(4-benzoyl    phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-4-isopropyl-3-(2-(((S)-1-(5-phenyl-1,3,4-thiadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (4S)-4-isopropyl-3-(2-(1-(5-phenylpyrimidin-2-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;-   3-(5-fluoro-2-((1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (S)-4-isopropyl-3-(2-(((S)-1-(1-(3-methoxyphenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (S)-3-(2-(((S)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-4-isopropyl-3-(2-(((S)-1-(3-(m-tolyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (S)-3-(2-(((S)-1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-((S)-1-(5-(4-fluoro-2-methylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-4-Isopropyl-3-{2-[(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amino]-pyrimidin-4-yl}-oxazolidin-2-one;-   (S)-4-isopropyl-3-(2-((S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;-   (S)-3-(2-((S)-1-(2-fluoro-4-isopropylphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-((S)-1-(4-isobutoxy-3-methylphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-(((S)-1-(4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(5-fluoro-2-(((S)-1-(4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   2-fluoro-N-(trans-4-hydroxycyclohexyl)-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide;-   (S)-3-(5-fluoro-2-((S)-1-(3-fluoro-4-(piperidine-1-carbonyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   N-cyclohexyl-2-fluoro-4-((S)-1-(5-fluoro-4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide;-   N-cyclohexyl-2-fluoro-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide;    and-   (S)-3-(5-fluoro-2-((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.

Selected compounds of the present invention include:

-   (S)-3-(2-(((S)-1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-(((S)-1-(4-((4,4-difluoropiperidin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(5-fluoro-2-(1-(4-phenoxyphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;-   (S)-3-(2-((S)-1-(4-(4-fluorophenoxy)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-((S)-1-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-(((S)-1-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-((S)-1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-((S)-1-(5-(4-fluorophenoxy)pyrazin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-4-isopropyl-3-(2-((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;    and-   (S)-3-(2-((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.

Selected compounds of the present invention include:

-   (S)-3-(2-(1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-5-fluoropyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one;-   (S)-3-(6-chloro-2-(1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;-   (S)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   2-chloro-N-cyclopentyl-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide;-   (S)-3-(2-((S)-1-(4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-((S)-1-(4-(4,7-diazaspiro[2.5]octan-4-ylmethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-((S)-1-(4-((4-acetylpiperazin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(2-(((S)-1-(4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;-   (S)-3-(5-fluoro-2-(((S)-1-(4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;    and-   2-fluoro-N-(trans-4-hydroxycyclohexyl)-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide.

ENUMERATED EMBODIMENTS Embodiment 1

A compound of formula (I)

wherein:each R¹ and R² is independently hydrogen, deuterium, halo, hydroxyl,NH₂, aryl, heteroaryl, or optionally substituted C₁₋₄ alkyl,

wherein said C₁₋₄ alkyl is optionally substituted with one to threesubstituents each independently selected from the group consisting of:halo, hydroxyl, and NH₂;

R^(3a) is hydrogen, deuterium, C₁₋₆ alkyl, phenyl, or benzyl andR^(3b) is hydrogen, deuterium, or C₁₋₆ alkyl; orR^(3a) and R^(3b) are joined together forming an optionally substituted3-7 membered cycloalkyl ring or an optionally substituted 4-7 memberedheterocyclic ring,

wherein said cycloalkyl and heterocyclic rings are each optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of: halo, hydroxyl, oxo, NH₂, and C₁₋₃ alkyl;

R^(4a) is hydrogen, C₁₋₆ alkyl, optionally substituted phenyl,optionally substituted benzyl, optionally substituted heteroaryl, ormethylene-dibenzene,

wherein said phenyl, benzyl, and heteroaryl rings are optionallysubstituted with one to three substituents each independently selectedfrom the group consisting of: halo, hydroxyl, cyano, nitro, C₁₋₃ alkoxy,C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, 5-6 membered heterocyclic, phenoxy, COOR^(b),SO₂R^(b), NHC(O)R^(b), and NR^(b)R^(b) and

R^(4b) is hydrogen, deuterium, or C₁₋₃ alkyl; orR^(4a) and R^(4b) are joined together forming an optionally substituted3-7 membered cycloalkyl ring or an optionally substituted 4-7 memberedheterocyclic ring,

wherein said cycloalkyl and heterocyclic rings are optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of: halo, hydroxyl, oxo, NH₂, and C₁₋₃ alkyl,

provided that only one of R^(3a) and R^(3b) and R^(4a) and R^(4b) arejoined together forming a ring;

R^(5a) is hydrogen or deuterium;R^(5b) is hydrogen, deuterium, methyl, ethyl, CD₃, CF₃, CH₂F, or CHF₂and R⁶ is optionally substituted C₁₋₆ alkyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedheterocyclic, or optionally substituted C₅₋₁₀ cycloalkyl,

wherein said C₁₋₆ alkyl is optionally substituted with one substituentselected from the group consisting of hydroxyl, C₁₋₃ alkoxy and —OR^(a);

wherein said aryl, heteroaryl, heterocyclic and C₅₋₁₀ cycloalkyl areoptionally substituted with one to three substituents each independentlyselected from the group consisting of: halo; hydroxyl; cyano; nitro;C₁₋₃ alkoxy; C₁₋₃ haloalkyl; C₁₋₃ haloalkoxy; C₁₋₆ alkyl; C₃₋₆cycloalkyl; phenyl optionally substituted with one to three substituentseach independently selected from the group consisting of: halo,hydroxyl, cyano, nitro, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 5-6 memberedheterocyclic, phenoxy, COOR^(b), SO₂R^(b), NHC(O)R^(b), and NR^(b)R^(b);5-6 membered heteroaryl; 5-6 membered heterocyclic optionallysubstituted with one to three substituents each independently selectedfrom the group consisting of: halo, hydroxyl, oxo, NH₂, and C₁₋₃ alkyl;—CH₂R^(a); —OR^(a); —C(O)R^(a); —NR^(a)R^(b); —COOR^(a); —SO₂R^(a);NHC(O)R^(a); and —SO₂NR^(b)R^(b); or

R^(5b) and R⁶ are joined together forming an optionally substituted C₃₋₇cycloalkyl group or an optionally substituted group of formula (a):

wherein n is 1, 2, or 3 and

said C₃₋₇ cycloalkyl and group of formula (a) are optionally substitutedwith one to three substituents each independently selected from thegroup consisting of: halo, hydroxyl, cyano, nitro, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, 5-6 membered heterocyclic, benzyloxy, COOR^(b), SO₂R^(b),NHC(O)R^(b), and NR^(b)R^(b);

each R^(a) is independently optionally substituted phenyl, optionallysubstituted heteroaryl, or optionally substituted 4-7 memberedheterocyclic,

wherein said phenyl and heteroaryl are optionally substituted with oneto three substituents each independently selected from the groupconsisting of halo, hydroxyl, cyano, nitro, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,C₁₋₃ haloalkoxy, and C₁₋₃ alkyl,

wherein said 4-7 membered heterocyclic is optionally substituted withone to three substituents each independently selected from the groupconsisting of halo, hydroxyl, oxo, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃haloalkoxy, and C₁₋₃ alkyl; and

each R^(b) is independently hydrogen or C₁₋₆ alkyl; or apharmaceutically acceptable salt thereof.

Embodiment 2

The compound according to embodiment 1 wherein R² is hydrogen; or apharmaceutically acceptable salt thereof.

Embodiment 3

The compound according to embodiment 2 wherein R¹ is hydrogen, halo, oroptionally substituted C₁₋₄ alkyl; or a pharmaceutically acceptable saltthereof.

Embodiment 4

The compound according to embodiment 3 wherein R¹ is hydrogen, fluoro,chloro, or methyl; or a pharmaceutically acceptable salt thereof.

Embodiment 5

The compound according to embodiment 4 wherein R^(3a) is hydrogen, C₁₋₆alkyl, phenyl, or benzyl and R^(3b) is hydrogen or C₁₋₆ alkyl; or apharmaceutically acceptable salt thereof.

Embodiment 6

The compound according to embodiment 5 wherein R^(3b) is hydrogen ormethyl; or a pharmaceutically acceptable salt thereof.

Embodiment 7

The compound according to embodiment 6 wherein R^(3a) is hydrogen,methyl, or phenyl; or a pharmaceutically acceptable salt thereof.

Embodiment 8

The compound according to embodiment 7 wherein R^(4a) is hydrogen, C₁₋₆alkyl, optionally substituted phenyl, optionally substituted benzyl,optionally substituted heteroaryl, or methylene-dibenzene,

wherein said phenyl, benzyl, and heteroaryl rings are optionallysubstituted with one to three substituents each independently selectedfrom the group consisting of: halo, hydroxyl, cyano, nitro, C₁₋₃ alkoxy,C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, 5-6 membered heterocyclic, phenoxy, COOR^(b),SO₂R^(b), NHC(O)R^(b), and NR^(b)R^(b) and

R^(4b) is hydrogen or C₁₋₃ alkyl; or a pharmaceutically acceptable saltthereof.

Embodiment 9

The compound according to embodiment 8 wherein R^(4b) is hydrogen ormethyl; or a pharmaceutically acceptable salt thereof.

Embodiment 10

The compound according to embodiment 9 wherein R^(4a) is hydrogen, C₁₋₄alkyl, optionally substituted phenyl, optionally substituted benzyl,optionally substituted heteroaryl, or methylene-dibenzene; or apharmaceutically acceptable salt thereof.

Embodiment 11

The compound according to embodiment 10 wherein R^(4a) is hydrogen,methyl, isopropyl, isobutyl, t-butyl, phenyl, 4-methoxyphenyl,4-fluorophenyl, benzyl, or methylene-dibenzene; or a pharmaceuticallyacceptable salt thereof.

Embodiment 12

The compound according to embodiment 11 wherein R^(5a) is H; or apharmaceutically acceptable salt thereof.

Embodiment 13

The compound according to embodiment 12 wherein R^(5b) is hydrogen,methyl, ethyl, or CF₃.

Embodiment 14

The compound according to embodiment 13 wherein R⁶ is isopropyl,optionally substituted aryl, optionally substituted pyrazolyl,optionally substituted pyridinyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzo[b][1,4]dioxinyl, or optionally substituted C₅₋₁₀cycloalkyl; or a pharmaceutically acceptable salt thereof.

Embodiment 15

A pharmaceutical composition comprising a compound according toembodiment 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or excipient.

Embodiment 16

A method for the treatment of a disease or disorder associated with amutant IDH protein having a neomorphic activity comprisingadministration of a therapeutically effective amount of a compoundaccording to embodiment 1, or a pharmaceutically acceptable saltthereof, to subject in need of thereof.

Embodiment 17

A method for the treatment of a disease or disorder associated with amutant IDH protein having a neomorphic activity comprisingadministration of a therapeutically effective amount of a compoundaccording to embodiment 1, or a pharmaceutically acceptable saltthereof, and another therapeutic agent to subject in need of thereof.

General Synthetic Procedures

The compounds of the present invention may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds of formula (I) may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the schemes described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, New York 1999). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selectionprocesses, as well as the reaction conditions and order of theirexecution, shall be consistent with the preparation of compounds offormula (I).

Those skilled in the art will recognize if a stereocenter exists in thecompounds of formula (I). Accordingly, the present invention includesboth possible stereoisomers and includes not only racemic compounds butthe individual enantiomers and/or diastereomers as well. When a compoundis desired as a single enantiomer or diastereomer, it may be obtained bystereospecific synthesis or by resolution of the final product or anyconvenient intermediate. Resolution of the final product, anintermediate, or a starting material may be effected by any suitablemethod known in the art. See, for example, “Stereochemistry of OrganicCompounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander(Wiley-Interscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Non-commercial aminoacids can be prepared following the procedures ofScheme 1. Conversion of ketone 1 to the correspondingimidazolidine-2,4-dione 2 followed by hydrolysis provides aminoacid 3.

When aminoalcohol, precursor of oxazolidinone, is not commerciallyavailable, it can be prepared from aminoacid 3 following the proceduresof Scheme 2. When R^(3a)═R^(3b), protected aminoester 5 is treated withan appropriate Grignard reagent to give protected aminoalcohol 6 whichgoes through basic or acidic deprotection step. When R^(3a)≠R^(3b),protected aminoacid 8 is converted into Weinreb amide 9 which is treatedwith different Grignard reagents sequentially to provide protectedaminoalcohol 10. Either basic or acidic deprotection of 10 gives 11.Insertion of CO unit into 7 or 11 to provide oxazolidinone 12 isaccomplished with several reagents, including (but not limited to)triphosgene, Et₂CO₃ or N—N′-darbonyldiimidazole, as shown in Scheme 2.

Oxazolidinone 12 is coupled with dihalogen-pyrimidine 13 in the presenceof NaH and the resulting 14 is treated with primary amine 15 underseveral different reaction conditions as shown in Scheme 3 to provide16.

Alternately intermediate 14 can be prepared by coupling the aminoalcohol 11 and dihalogen-pyrimidine 13 in the presence of a base such asdiisopropylethyl amine resulting in intermediate 17 which can be treatedwith triphosgene in the presence of a base such as 2,6-lutidineresulting in intermediate 14.

Methods of Use

The compounds of the present invention are inhibitors of a mutant IDHprotein having a neomorphic activity and are therefore useful in thetreatment of diseases or disorders associated with such proteinsincluding, but not limited to, cell proliferation disorders, such ascancer.

Examples of a mutant IDH protein having a neomorphic activity are mutantIDH1 and mutant IDH2. A neomorphic activity associated with mutant IDH1and mutant IDH2 is the ability to produce 2-hydroxyglutarate (2-HGneomorphic activity), specifically R-2-HG (R-2-HG neomorphic activity).Mutations in IDH1 associated with 2-HG neomorphic activity, specificallyR-2-HG neomorphic activity, include mutations at residues 97, 100, and132, e.g. G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V.Mutations in IDH2 associated with 2-HG neoactivity, specifically R-2-HGneomorphic activity, include mutations at residues 140 and 172, e.g.R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.

Cell-proliferation disorders associated with a mutant IDH protein havinga neomorphic activity include, but are not limited to, cancer. Examplesof such cancers include Acute Lymphoblastic Leukemia, Adult; AcuteLymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult;Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood;AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer;Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; BileDuct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood;Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain StemGlioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma,Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor,Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor,Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; BrainTumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; BrainTumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor,Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; BreastCancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids,Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor,Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell;Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary;Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/MalignantGlioma, Childhood; Cervical Cancer; Childhood Cancers; ChronicLymphocytic Leukemia; Chronic Myelogenous Leukemia; ChronicMyeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths;Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma;Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian;Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family ofTumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ CellTumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma;Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach)Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal CarcinoidTumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor,Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor;Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway andHypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular(Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer,Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma,Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer;Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma;Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; KidneyCancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, AcuteLymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood;Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood;Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia,Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary);Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; LungCancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; LymphoblasticLeukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma,AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma,Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's,Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma,Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma,Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central NervousSystem; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; MalignantMesothelioma, Adult; Malignant Mesothelioma, Childhood; MalignantThymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular;Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous NeckCancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome,Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides;Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; MyeloidLeukemia, Childhood Acute; Myeloma, Multiple; MyeloproliferativeDisorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer;Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma;Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood;Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer;Oral Cancer, Childhood; Oral Cavity and Lip Cancer; OropharyngealCancer; steosarcoma/Malignant Fibrous Histiocytoma of Bone; OvarianCancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor;Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; PancreaticCancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus andNasal Cavity Cancer; Parathyroid Cancer; Penile Cancer;Pheochromocytoma; Pineal and Supratentorial Primitive NeuroectodermalTumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/MultipleMyeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer;Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma;Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult;Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; RenalCell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis andUreter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma,Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood;Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma(Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma,Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, SoftTissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood;Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell LungCancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft TissueSarcoma, Childhood; Squamous Neck Cancer with Occult Primary,Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer,Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood;T-Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood;Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood;Transitional Cell Cancer of the Renal Pelvis and Ureter; TrophoblasticTumor, Gestational; Unknown Primary Site, Cancer of, Childhood; UnusualCancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer;Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway andHypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macroglobulinemia; and Wilms' Tumor.

In another embodiment the cancer associated with a mutant IDH proteinhaving a neomorphic activity is brain cancer, such as astrocytic tumor(e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma,diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplasticastrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma,secondary glioblastoma, primary adult glioblastoma, and primarypediatric glioblastoma); oligodendroglial tumor (e.g.,oligodendroglioma, and anaplastic oligodendroglioma); oligoastrocytictumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma);ependymoma (e.g., myxopapillary ependymoma, and anaplastic ependymoma);medulloblastoma; primitive neuroectodermal tumor, schwannoma,meningioma, meatypical meningioma, anaplastic meningioma; and pituitaryadenoma. In another embodiment, the brain cancer is glioma, glioblastomamultiforme, paraganglioma, or suprantentorial primordial neuroectodermaltumors (sPNET).

In another embodiment the cancer associated with a mutant IDH proteinhaving a neomorphic activity is leukemia, such as acute myeloid leukemia(AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia(CML), myeloproliferative neoplasm (MPN), MDS.MPN including chronicmyelomonocytic leukemia, post MDS AML, post MPN AML, post MDS/MPN AML,del(5q)-associated high risk MDS or AML, blast-phase chronic myelogenousleukemia, angioimmunoblastic lymphoma and acute lymphoblastic leukemia.

In another embodiment the cancer associated with a mutant IDH proteinhaving a neomorphic activity is skin cancer, including melanoma.

In another embodiment the cancer associated with a mutant IDH proteinhaving a neomorphic activity is prostate cancer, thyroid cancer, coloncancer, or lung cancer.

In another embodiment the cancer associated with a mutant IDH proteinhaving a neomorphic activity is sarcoma, including centralchondrosarcoma, central and periosteal chondroma, and fibrosarcoma.

In another embodiment the cancer associated with a mutant IDH proteinhaving a neomorphic activity is cholangiocarcinoma.

Another disease or disorder associated with a mutant IDH protein havingR-2-HG neomorphic activity is D-2-hydroxyglutaric aciduria.

Another disease or disorder associated with a mutant IDH protein havingR-2-HG neomorphic activity is Diller disease and Mafucci syndrome.

As used herein the term “neomorphic activity” refers to a gain of novelactivity of a protein that the wild-type protein does not have or doesnot exhibit to a significant degree. For example, a neomorphic activityassociated with a mutant form of IDH1 and IDH2 is the ability to reducealpha-ketoglutarate to 2-hydroxyglutarate (i.e. 2-HG, specificallyR-2-HG). The wild type form of IDH1 and IDH2 does not have the abilityto reduce alpha-ketoglutarate to 2-hydroxyglutarate (i.e. 2-HG,specifically R-2-HG) or if it does have this ability, it does notproduce significant (i.e. harmful or disease causing) amounts of 2-HG.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, the term “therapeutically effective amount” in referenceto a compound of the invention means an amount of the compoundsufficient to treat the subject's disease or condition, but low enoughto avoid serious sides effects (at a reasonable benefit/risk ratio)within the scope of sound medical judgment. A therapeutically effectiveamount of a compound will vary with the particular compound chosen (e.g.consider the potency, efficacy, and half-life of the compound); theroute of administration chosen; the condition being treated; theseverity of the condition being treated; the age, size, weight, andphysical condition of the subject being treated; the medical history ofthe subject being treated; the duration of the treatment; the nature ofthe concurrent therapy; the desired therapeutic effect; and like factorsand can be routinely determined by the skilled artisan.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

The compounds of the present invention may be administered by anysuitable route including oral and parenteral administration. Parenteraladministration is typically by injection or infusion and includesintravenous, intramuscular, and subcontaneous injection or infusion.

The compounds of the invention may be administered once or according toa dosing regimen wherein a number of doses are administered at varyingintervals of time for a given period of time. For example, doses may beadministered one, two, three, or four times per day. Doses may beadministered until the desired therapeutic effect is achieved orindefinitely to maintain the desired therapeutic effect. Suitable dosingregimens for a compound of the invention depend on the pharmacokineticproperties of that compound, such as absorption, distribution and halflife which can be determined by the skilled artisan. In addition,suitable dosing regimens, including the duration such regimens areadministered, for a compound of the invention depend on the disease orcondition being treated, the severity of the disease or condition, theage and physical condition of the subject being treated, the medicalhistory of the subject being treated, the nature of concurrent therapy,the desired therapeutic effect, and like factors within the knowledgeand expertise of the skilled artisan. It will be further understood bysuch skilled artisans that suitable dosing regimens may requireadjustment given an individual subject's response to the dosing regimenor over time as the individual subject needs change. Typical dailydosages may vary depending upon the particular route of administrationchosen. Typical daily dosages for oral administration, to a humanweighing approximately 70 kg would range from about 5 mg to about 500 mgof a compound of formula (I).

One embodiment of the present invention provides for a method oftreating a disease or disorder associated with a mutant form of IDHhaving a neomorphic activity comprising administration of atherapeutically effective amount of a compound of formula (I) to asubject in need of treatment thereof. In one embodiment, the disease ordisorder associated with a mutant form of IDH having a neomorphicactivity is a cell proliferation disorder. In another embodiment, thecell proliferation disorder is cancer. In another embodiment, the canceris a cancer associated with mutant IDH1 having 2-HG neomorphic activityor mutant IDH2 having 2-HG neomorphic activity. In another embodimentthe neomorphic activity is R-2-HG neomorphic activity. In anotherembodiment the cancer is associated with mutant IDH1 having 2-HG orR-2-HG neomorphic activity having a mutation at residues 97, 100, or132, such as G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V.In another embodiment the cancer is associated with mutant IDH2 having2-HG or R-2-HG neomorphic activity having a mutation at residues 140 or172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W. Inanother embodiment the cancer is brain cancer, leukemia, skin cancer,prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma.In another embodiment the cancer is glioma, glioblastoma multiforme,paraganglioma, suprantentorial primordial neuroectodermal tumors, acutemyeloid leukemia, myelodysplastic syndrome, chronic myelogenousleukemia, melanoma, prostate, thyroid, colon, lung, centralchondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma,and cholangiocarcinoma.

Another embodiment of the present invention provides for a method oftreating a disease or disorder associated with a mutant form of IDHhaving R-2-HG neomorphic activity comprising administration of atherapeutically effective amount of a compound according to formula (I)to a subject in need thereof wherein the disease or disorder isD-2-hydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.

Another embodiment of the present invention provides for the use of acompound of formula (I) in therapy. In a further embodiment the therapyis a disease or disorder associated with a mutant form of IDH having aneomorphic activity. In another embodiment the therapy is a cellproliferation disorder associated with a mutant form of IDH having aneomorphic activity. In another embodiment the therapy is cancer. Inanother embodiment the therapy is a cancer associated with a mutant IDHprotein having a neomorphic activity, such as mutant IDH1 having 2-HGneomorphic activity or mutant IDH2 having 2-HG neomorphic activity. Inanother embodiment the neomorphic activity is R-2-HG neomorphicactivity. In another embodiment the cancer is associated with mutantIDH1 having 2-HG or R-2-HG neomorphic activity having a mutation atresidues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S,R132G, R132L, and R132V. In another embodiment the cancer is associatedwith mutant IDH2 having 2-HG or R-2-HG neomorphic activity having amutation at residue at residues R140 or 172, e.g. R140Q, R140G, R172K,R172M, R172S, R172G, and R172W. In another embodiment the cancer isbrain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer,colon cancer, lung cancer or sarcoma. In another embodiment the canceris glioma, glioblastoma multiforme, paraganglioma, suprantentorialprimordial neuroectodermal tumors, acute myeloid leukemia,myelodysplastic syndrome, chronic myelogenous leukemia, melanoma,prostate, thyroid, colon, lung, central chondrosarcoma, central andperiosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.

Another embodiment of the present invention provides for the use of acompound of formula (I) in therapy wherein the therapy isD-2-hydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.

Another embodiment of the present invention provides for the use of acompound according to formula (I) in the manufacture of a medicament forthe treatment of disease or disorder associated with a mutant form ofIDH having a neomorphic activity. In one embodiment the disease ordisorder associated with a mutant form of IDH having a neomorphicactivity is a cell proliferation disorder. In another embodiment, thecell proliferation disorder is cancer. In another embodiment the canceris a cancer associated with a mutant IDH protein having a neomorphicactivity, such as mutant IDH1 having 2-HG neomorphic activity or mutantIDH2 having 2-HG neomorphic activity. In another embodiment theneomorphic activity is R-2-HG neomorphic activity. In another embodimentthe cancer is associated with mutant IDH1 having 2-HG or R-2-HGneomorphic activity having a mutation at residues 97, 100, or 132, suchas G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V. In anotherembodiment the cancer is associated with mutant IDH2 having 2-HG orR-2-HG neomorphic activity having a mutation at residue at residues 140or 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W. Inanother embodiment the cancer is brain cancer, leukemia, skin cancer,prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma.In another embodiment the cancer is glioma, glioblastoma multiforme,paraganglioma, suprantentorial primordial neuroectodermal tumors, acutemyeloid leukemia, myelodysplastic syndrome, chronic myelogenousleukemia, melanoma, prostate, thyroid, colon, lung, centralchondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma,and cholangiocarcinoma.

Another embodiment of the present invention provides for the use of acompound according to formula (I) in the manufacture of a medicament forthe treatment of disease or disorder associated with a mutant form ofIDH having R-2-HG neomorphic activity wherein the disease or disorder isD-2-hydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.

Compositions

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier or excipient.

The pharmaceutical compositions of the invention may be prepared andpackaged in bulk form wherein a therapeutically effective amount of acompound of the invention can be extracted and then given to a subject,such as with powders or syrups. Alternatively, the pharmaceuticalcompositions of the invention may be prepared and packaged in unitdosage form wherein each physically discrete unit contains atherapeutically effective amount of a compound of the invention. Whenprepared in unit dosage form, the pharmaceutical compositions of theinvention typically contain from about 5 mg to 500 mg of a compound offormula (I).

As used herein the term “pharmaceutically acceptable carrier orexcipient” means a pharmaceutically acceptable material, composition orvehicle that, for example, are involved in giving form or consistency tothe pharmaceutical composition. Each excipient must be compatible withthe other ingredients of the pharmaceutical composition when commingledsuch that interactions which would substantially reduce the efficacy ofthe compound of the invention when administered to a subject andinteractions which would result in pharmaceutical compositions that arenot pharmaceutically acceptable are avoided. In addition, each excipientmust, of course, be of sufficiently high purity to render itpharmaceutically acceptable.

The compound of the invention and the pharmaceutically acceptablecarrier or excipient(s) will typically be formulated into a dosage formadapted for administration to the subject by the desired route ofadministration. For example, dosage forms include those adapted for (1)oral administration such as tablets, capsules, caplets, pills, troches,powders, syrups, elixirs, suspensions, solutions, emulsions, sachets,and cachets; and (2) parenteral administration such as sterilesolutions, suspensions, and powders for reconstitution. Suitablepharmaceutically acceptable excipients will vary depending upon theparticular dosage form chosen. In addition, suitable pharmaceuticallyacceptable excipients may be chosen for a particular function that theymay serve in the composition. For example, certain pharmaceuticallyacceptable excipients may be chosen for their ability to facilitate theproduction of uniform dosage forms. Certain pharmaceutically acceptableexcipients may be chosen for their ability to facilitate the productionof stable dosage forms. Certain pharmaceutically acceptable excipientsmay be chosen for their ability to facilitate the carrying ortransporting of the compound or compounds of the invention, onceadministered to the subject, from one organ or portion of the body toanother organ or another portion of the body. Certain pharmaceuticallyacceptable excipients may be chosen for their ability to enhance patientcompliance.

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: diluents, lubricants, binders, disintegrants,fillers, glidants, granulating agents, coating agents, wetting agents,solvents, co-solvents, suspending agents, emulsifiers, sweeteners,flavoring agents, flavor masking agents, coloring agents, anti-cakingagents, hemectants, chelating agents, plasticizers, viscosity increasingagents, antioxidants, preservatives, stabilizers, surfactants, andbuffering agents.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically acceptable carriers andexcipients in appropriate amounts for the use in the invention. Inaddition, there are a number of resources available to the skilledartisan, which describe pharmaceutically acceptable carriers andexcipients and may be useful in selecting suitable pharmaceuticallyacceptable carriers and excipients. Examples include Remington'sPharmaceutical Sciences (Mack Publishing Company), The Handbook ofPharmaceutical Additives (Gower Publishing Limited), and The Handbook ofPharmaceutical Excipients (the American Pharmaceutical Association andthe Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some methodscommonly used in the art are described in Remington's PharmaceuticalSciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage formsuch as a tablet or capsule comprising a therapeutically effectiveamount of a compound of the invention and a diluent or filler. Suitablediluents and fillers include lactose, sucrose, dextrose, mannitol,sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinizedstarch), cellulose and its derivatives, (e.g. microcrystallinecellulose), calcium sulfate, and dibasic calcium phosphate. The oralsolid dosage form may further comprise a binder. Suitable bindersinclude starch (e.g. corn starch, potato starch, and pre-gelatinizedstarch) gelatin, acacia, sodium alginate, alginic acid, tragacanth, guargum, povidone, and cellulose and its derivatives (e.g. microcrystallinecellulose). The oral solid dosage form may further comprise adisintegrant. Suitable disintegrants include crospovidone, sodium starchglycolate, croscarmelose, alginic acid, and sodium carboxymethylcellulose. The oral solid dosage form may further comprise a lubricant.Suitable lubricants include stearic acid, magnesium stearate, calciumstearate, and talc.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The composition can also be prepared to prolong orsustain the release as, for example, by coating or embedding particulatematerial in polymers, wax, or the like.

The compounds of the invention may also be coupled with soluble polymersas targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyrancopolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of theinvention may be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example polylactic acid,polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanacrylates and cross-linked oramphipathic block copolymers of hydrogels.

In another aspect, the invention is directed to a liquid oral dosageform. Oral liquids such as solution, syrups and elixirs can be preparedin dosage unit form so that a given quantity contains a predeterminedamount of a compound of the invention. Syrups can be prepared bydissolving the compound of the invention in a suitably flavored aqueoussolution; while elixirs are prepared through the use of a non-toxicalcoholic vehicle. Suspensions can be formulated by dispersing thecompound of the invention in a non-toxic vehicle. Solubilizers andemulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylenesorbitol ethers, preservatives, flavor additives such as peppermint oilor other natural sweeteners or saccharin or other artificial sweetenersand the like can also be added.

In another aspect, the invention is directed to parenteraladministration. Pharmaceutical compositions adapted for parenteraladministration include aqueous and non-aqueous sterile injectionsolutions which may contain anti-oxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Thecompositions may be presented in unit-dose or multi-dose containers, forexample sealed ampoules and vials, and may be stored in a freeze dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example water for injections, immediately prior touse. Extemporaneous injection solutions and suspensions may be preparedfrom sterile powders, granules and tablets.

Combinations

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagent(s). The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agent(s).

In one embodiment, the invention provides a product comprising acompound of formula (I) and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a disease ordisorder associated with a mutant form of IDH. Products provided as acombined preparation include a composition comprising the compound offormula (I) and the other therapeutic agent(s) together in the samepharmaceutical composition, or the compound of formula (I) and the othertherapeutic agent(s) in separate form, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) and another therapeutic agent(s).Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable excipient, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of formula (I). In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic agent may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

Accordingly, the invention provides the use of a compound of formula (I)for treating a disease or disorder associated with a mutant form of IDH,wherein the medicament is prepared for administration with anothertherapeutic agent. The invention also provides the use of anothertherapeutic agent for treating a disease or disorder associated with amutant form of IDH, wherein the medicament is administered with acompound of formula (I).

The invention also provides a compound of formula (I) for use in amethod of treating a disease or disorder associated with a mutant formof IDH, wherein the compound of formula (I) is prepared foradministration with another therapeutic agent. The invention alsoprovides another therapeutic agent for use in a method of treating adisease or disorder associated with a mutant form of IDH, wherein theother therapeutic agent is prepared for administration with a compoundof formula (I). The invention also provides a compound of formula (I)for use in a method of treating a disease or disorder associated with amutant form of IDH, wherein the compound of formula (I) is administeredwith another therapeutic agent. The invention also provides anothertherapeutic agent for use in a method of treating a disease or disorderassociated with a mutant form of IDH, wherein the other therapeuticagent is administered with a compound of formula (I).

The invention also provides the use of a compound of formula (I) fortreating a disease or disorder associated with a mutant form of IDH,wherein the patient has previously (e.g. within 24 hours) been treatedwith another therapeutic agent. The invention also provides the use ofanother therapeutic agent for treating a disease or disorder associatedwith a mutant form of IDH, wherein the patient has previously (e.g.within 24 hours) been treated with a compound of formula (I).

In one embodiment, the other therapeutic agent is selected from:vascular endothelial growth factor (VEGF) receptor inhibitors,topoisomerase II inhibitors, smoothen inhibitors, alkylating agents,anti-tumor antibiotics, anti-metabolites, retinoids, and other cytotoxicagents.

Examples of vascular endothelial growth factor (VEGF) receptorinhibitors include, but are not limited to, bevacizumab (sold under thetrademark Avastin® by Genentech/Roche), axitinib,(N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide,also known as AG013736, and described in PCT Publication No. WO01/002369), Brivanib Alaninate((S)—((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate,also known as BMS-582664), motesanib(N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide,and described in PCT Publication No. WO 02/066470), pasireotide (alsoknown as SOM230, and described in PCT Publication No. WO 02/010192), andsorafenib (sold under the tradename Nexavar®).

Examples of topoisomerase II inhibitors, include but are not limited to,etoposide (also known as VP-16 and Etoposide phosphate, sold under thetradenames Toposar®, VePesid® and Etopophos®), and teniposide (alsoknown as VM-26, sold under the tradename Vumon®).

Examples of alkylating agents, include but are not limited to,temozolomide (sold under the tradenames Temodar® and Temodal® bySchering-Plough/Merck), dactinomycin (also known as actinomycin-D andsold under the tradename Cosmegen®), melphalan (also known as L-PAM,L-sarcolysin, and phenylalanine mustard, sold under the tradenameAlkeran®), altretamine (also known as hexamethylmelamine (HMM), soldunder the tradename Hexalen®), carmustine (sold under the tradenameBiCNU®), bendamustine (sold under the tradename Treanda®), busulfan(sold under the tradenames Busulfex® and Myleran®), carboplatin (soldunder the tradename Paraplatin®), lomustine (also known as CCNU, soldunder the tradename CeeNU®), cisplatin (also known as CDDP, sold underthe tradenames Platinol® and Platinol®-AQ), chlorambucil (sold under thetradename Leukeran®), cyclophosphamide (sold under the tradenamesCytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC andimidazole carboxamide, sold under the tradename DTIC-Dome®), altretamine(also known as hexamethylmelamine (HMM) sold under the tradenameHexalen®), ifosfamide (sold under the tradename Ifex®), procarbazine(sold under the tradename Matulane®), mechlorethamine (also known asnitrogen mustard, mustine and mechloroethamine hydrochloride, sold underthe tradename Mustargen®), streptozocin (sold under the tradenameZanosar®), thiotepa (also known as thiophosphoamide, TESPA and TSPA, andsold under the tradename Thioplex®.

Examples of anti-tumor antibiotics include, but are not limited to,doxorubicin (sold under the tradenames Adriamycin® and Rubex®),bleomycin (sold under the tradename Lenoxane®), daunorubicin (also knownas dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride,sold under the tradename Cerubidine®), daunorubicin liposomal(daunorubicin citrate liposome, sold under the tradename DaunoXome®),mitoxantrone (also known as DHAD, sold under the tradename Novantrone®),epirubicin (sold under the tradename Ellence™), idarubicin (sold underthe tradenames Idamycin®, Idamycin PFS®), and mitomycin C (sold underthe tradename Mutamycin®).

Examples of anti-metabolites include, but are not limited to, claribine(2-chlorodeoxyadenosine, sold under the tradename Leustatin®),5-fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (soldunder the tradename Purinethol®), pemetrexed (sold under the tradenameAlimta®), cytarabine (also known as arabinosylcytosine (Ara-C), soldunder the tradename Cytosar-U®), cytarabine liposomal (also known asLiposomal Ara-C, sold under the tradename DepoCyt™), decitabine (soldunder the tradename Dacogen®), hydroxyurea (sold under the tradenamesHydrea®, Droxia™ and Mylocel™), fludarabine (sold under the tradenameFludara®), floxuridine (sold under the tradename FUDR®), cladribine(also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradenameLeustatin™), methotrexate (also known as amethopterin, methotrexatesodim (MTX), sold under the tradenames Rheumatrex® and Trexall™), andpentostatin (sold under the tradename Nipent®).

Examples of retinoids include, but are not limited to, alitretinoin(sold under the tradename Panretin®), tretinoin (all-trans retinoicacid, also known as ATRA, sold under the tradename Vesanoid®),Isotretinoin (13-cis-retinoic acid, sold under the tradenames Accutane®,Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®,Isotret®, and Sotret®), and bexarotene (sold under the tradenameTargretin®).

Examples of other cytotoxic agents include, but are not limited to,arsenic trioxide (sold under the tradename Trisenox®), asparaginase(also known as L-asparaginase, and Erwinia L-asparaginase, sold underthe tradenames Elspar® and Kidrolase®).

Intermediates and Examples

The following examples are intended to be illustrative only and notlimiting in any way. Unless otherwise noted, the following Intermediatesand Examples were purified vial silica gel column chromatograph usingRediSep® Rf columns from Teledyne Isco, Inc. Abbreviations used arethose conventional in the art or the following:

ACN acetonitrialBSA bovine serum albumin

C Celsius

CDI 1,1′-carbonyldiimidazoled doubletdd doublet of doubletsDAST diethylaminosulfur trifluorideDEAD diethyl azodicarboxylate

DIPEA NN-diisopropylethylamine DMF N,N-dimethylformamide

DMSO dimethylsulfoxideDTT dithiothreitolEtOAc ethyl acetateEtOH ethanolg gramh hour(s) HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphateHEPES 4-(2-hydroxyethyl)-1-piperazineethylanesulfonic acidHPLC high pressure liquid chromatography

Hunig's Base NN-diisopropylethylamine

kg kilogramL literLC liquid chromatographyLCMS liquid chromatography and mass spectrometryMeOH methanolMS mass spectrometrym multipletmin minutesmL milliliter(s)μM micromolarm/z mass to charge rationm nanometernM nanomolarN normalNADPH nicotinamide adenine dinucleotide phosphate

NMP N-methylpyrrolidone

NMR nuclear magnetic resonancePdCl₂(dppf).CH₂Cl₂1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complexpTsOH p-toluenesulfonic acidrac racemicRt retention times singletsat. saturatedt tripletTBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborateTCEP tris(2-carboxyethyl)phosphineTEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromatographyTMS-CN trimethylsilyl cyanide

Instrumentation LCMS:

LCMS data (also reported herein as simply MS) were recorded using aWaters System (Acuity UPLC and a Micromass ZQ mass spectrometer; Column:Acuity HSS C18 1.8-micron, 2.1×50 mm; gradient: 5-95% acetonitrile inwater with 0.05% TFA over a 1.8 min period; flow rate 1.2 mL/min;molecular weight range 200-1500; cone Voltage 20 V; column temperature50° C.). All masses reported are those of the protonated parent ionsunless recorded otherwise.

High Resolution Mass Spectrometry (HRMS):

HRMS Method A: ESI-MS data were recorded using a Synapt G2HDMS (TOF massspectrometer, Waters) with electrospray ionization source. Theresolution of the MS system was approximately 15000. Leucine Enkephalinwas used as lock mass (internal standards) infused from lockspary probe.The compound was infused into the mass spectrometer by UPLC (Acquity,Waters) from sample probe. The separation was performed on Acquity UPLCBEH C18 1×50 mm column at 0.2 mL/min flow rate with the gradient from 5%to 95% in 3 min. Solvent A was Water with 0.1% Formic Acid and solvent Bwas Acetonitrile with 0.1% Formic Acid. The mass accuracy of the systemhas been found to be <5 ppm with lock mass.

HRMS Method B: LC-MS/ESI-MS data were recorded on an Acquity G2 XevoQTof—Rs(FWHM)>20000 Accuracy<5 ppm. The separation was performed onAcquity CSH 1.7 μm 2.1×50 mm—50° C. column Eluent A: Water+3.75 mMammonium acetate. Eluent B: Acetonitrile. Gradient: from 2 to 98% B in4.4 min—flow 1.0 mL/min.

HRMS methods A and B are referred to throughout as HRMS(A) or HRMS(B),respectively.

INTERMEDIATES Intermediate A (R)-4-isobutyloxazolidin-2-one

To a cooled (4° C.) solution of (R)-2-amino-4-methylpentan-1-ol (2.98 g,25.4 mmol) and triethylamine (7.6 mL, 54 mmol, 2.1 equiv) in CH₂Cl₂ (80mL) was added dropwise a solution of triphosgene (2.52 g, 8.49 mmol,0.334 equiv) in 10 ml of CH₂Cl₂ over 30 min. The reaction mixture wasstirred at 4° C. for 15 min, warmed up to room temperature and stirredfor an additional 1 h. The mixture was treated with saturated NH₄Cl (25mL), followed by CH₂Cl₂ (50 mL) and the resulting mixture was stirredfor 20 min. The layers were separated and the organic layer was washedwith water. The combined aqueous layers were extracted with CH₂Cl₂ (50mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to give (R)-4-isobutyloxazolidin-2-one (3.22 g) in 88%yield. The crude product was used for the next reaction withoutpurification. ¹H NMR (400 MHz, CD₃OD) δ 4.53-4.47 (m, 1H), 4.00-3.92 (m,2H), 1.67 (ddq, J=13, 8.0, 6.5 Hz, 1H), 1.56-1.48 (m, 1H), 1.40-1.32 (m,1H), 0.95 (d, J=6.1 Hz, 3H), 0.93 (d, J=6.1 Hz, 3H).

The Intermediates in Table 1 were prepared by a method similar to theone described for the preparation of Intermediate A.

TABLE 1

Intermediate B

Intermediate C

Intermediate D

Intermediate E

Intermediate F

Intermediate G

Intermediate H

Intermediate I

Intermediate J

Intermediate K

Intermediate L

TABLE 2 Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 1. Intermediate: Name ¹H NMR (400 MHz) δppm LCMS B: (S)-4-isobutyloxazolidin-2- (CDCl₃) 6.59 (br s, 1 H),4.53-4.48 no UV signal one (m, 1 H), 4.01-3.92 (m, 2 H), 1.71- 1.54 (m,2 H), 1.42-1.35 (m, 1 H), 0.94 (d, J = 6.5 Hz, 3 H), 0.93 (d, J = 6.5Hz, 3 H). C: (S)-4-tert-butyloxazolidin-2- (CD₃OD) 4.37 (t, J = 9.1 Hz,1 H), 4.23 no UV signal one (dd, J = 9.1, 5.6 Hz, 1 H), 3.61 (dd, J =9.1, 5.6 Hz, 1 H), 0.90 (s, 9 H) D: (4S,5R)-5-methyl-4- (CD₃OD) δ7.42-7.32 (m, 3 H), 7.27- no UV signal phenyloxazolidin-2-one 7.24 (m, 2H), 5.05 (dq, J = 8.0, 6.4 Hz, 1 H), 4.98 (d, J = 8.0 Hz, 1 H), 0.89 (d,J = 6.5 Hz, 3 H) E: (S)-4-(pyridin-3- MS m/z yl)oxazolidin-2-one 165.1(M + H)⁺ F: (S)-4-(pyridin-2- (CDCl₃) 8.62 (dt, J = 5.4, 1.1 Hz, 1 H),HRMS(B) yl)oxazolidin-2-one 7.80 (td, J = 7.8, 1.5 Hz, 1 H), 7.45 (d,m/z 165.0663 J = 7.5 Hz, 1 H), 7.33-7.28 (m, 1 H), (M + H)⁺ 6.40 (br s,1 H), 5.12 (dd, J = 8.8, 5.8 Hz, 1 H), 4.86 (t, J = 9.0 Hz, 1 H), 4.43(dd, J = 8.5, 5.5 Hz, 1 H) G: (S)-4-(pyridin-4- (CDCl₃) 8.67-8.66 (m, 2H), 7.36- HRMS(B) yl)oxazolidin-2-one 7.34 (m, 2 H), 6.50 (br s, 1 H),5.04- m/z 165.0664 5.00 (m, 1 H), 4.80 (t, J = 8.8 Hz, 1 H), (M + H)⁺4.16 (dd, J = 8.5, 6.5 Hz, 1 H) H: (S)-4-methyl-4- (CDCl₃) 7.45-7.33 (m,5 H), 6.10 (br HRMS(B) phenyloxazolidin-2-one s, 1 H), 4.39 (q, J = 8.4Hz, 2 H), 1.79 m/z 178.0871 (s, 3 H) (M + H)⁺ I:4,4-dimethyloxazolidin-2-one (CDCl₃) 4.96 (br s, 1 H), 4.12 (s, 2 H), noUV signal 1.40 (s, 6 H) J: (S)-4-methyl-4- (CDCl₃) 7.33-7.19 (m, 5 H),6.86 (br MS m/z phenyloxazolidin-2-one s, 1 H), 4.32-4.27 (m, 2 H), 1.67(s, 3 177.9 (M + H) H)⁺ K: (R)-4-(4-fluorophenyl)-4- (CDCl₃) δ 7.41-7.36(m, 2 H), 7.14- MS m/z methyloxazolidin-2-one 7.08 (m, 2 H), 6.06 (br s,1 H), 4.39 (d, 195.9 (M + J = 8.3 Hz, 1 H), 4.33 (d, J = 8.3 Hz, 1 H)+H), 1.78 (s, 3 H) L: 3-oxa-1-azaspiro[4.4]nonan- (CDCl₃) δ 5.62 (br s, 1H), 4.25 (s, 2 no UV signal 2-one H), 1.90-1.65 (m, 8 H)

Intermediate M 4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one

Step 1: Preparation of 4-(amino(phenyl)methyl)tetrahydro-2H-pyran-4-ol

To dihydro-2H-pyran-4(3H)-one (1001 mg, 10 mmol) and triethylamine(0.279 mL, 2.00 mmol) was slowly added TMS-CN (1190 mg, 12.00 mmol)[Caution: exothermic reaction]. After stirring for 1 hour, the mixturewas concentrated under reduced pressure. The residue, dissolved indiethyl ether (10 mL), was added dropwise to phenylmagnesium bromide (3Msolution in diethyl ether, 4.33 mL, 13.00 mmol). Additional ˜5 mL ofdiethyl ether was added and the suspension was stirred for ˜4 hour. Tothe reaction mixture was added very slowly MeOH (3.0 mL), followed bythe careful and slow additions of NaBH₄ (454 mg, 12.00 mmol) and MeOH(12 mL) in portions (gas development observed). The reaction mixture wasstirred overnight and water (˜6 mL) was added carefully, followed by 10%aqueous HCl solution (˜20 mL). The mixture was vigrously stirred for 4hour and diethyl ether was added. The separated organic layer wasextracted with 10% aqueous HCl solution (1× ˜20 mL). The combinedaqueous layers were washed with diethylether (2×). The acidic layerswere made basic by the addition of 6N aqueous NaOH solution. The milkywhite mixture was extracted with DCM (1×), ethyl acetate/THF (1:1; 1×)and ethyl acetate (2×). The organic layers (DCM and ethyl acetatesolutions independently) were washed with saturated aqueous NaHCO₃solution, dried over Na₂SO₄, filtered off and concentrated under reducedpressure providing crude4-(amino(phenyl)methyl)tetrahydro-2H-pyran-4-ol, which was directly usedin the next reaction without further purification.

Yellowish liquid. Yield: 451 mg. LCMS m/z 208.2 (M+H)⁺, Rt 0.29 min.

Step 2: Preparation of 4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one

To a mixture of CDI (388 mg, 2.394 mmol) in THF (1.5 mL) was addedslowly a solution of 4-(amino(phenyl)methyl)tetrahydro-2H-pyran-4-ol(451 mg, 2.176 mmol) in THF (3 mL). The mixture was stirred under argonfor ˜5 hours. The mixture was diluted with saturated aqueous NaHCO₃solution and DCM. The separated aqueous layer was extracted with DCM(2×) and the combined organic layers were washed with 0.5N aqueous HClsolution and brine, dried over sodium sulfate, filtered off andconcentrated under reduced pressure. The residue was purified by columnchromatography [SiO₂, 12 g, 0-100% heptane/ethyl acetate] providing4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one as a white solid. Yield:330 mg. LCMS m/z 234.1 (M+H)⁺; Rt 0.52 min.

Intermediate N (S)-4-(biphenyl-4-yl)oxazolidin-2-one

Step 1: Preparation of Vinylbiphenyl

To a suspension of methyltriphenylphosphonium bromide (5.10 g, 14.27mmol) in THF (26 mL) was slowly added potassium tert-butoxide (1Msolution in THF, 14.27 mL) over ˜20 min at 0° C. The reaction mixturewas allowed to warm up to room temperature and stirred for 10 min. Themixture was cooled to 0° C. and a solution of 4-biphenylcarbaldehyde(2.0 g, 10.98 mmol) in THF (9 mL) was added over 20 min. The reactionmixture was allowed to warm up to room temperature and stirred for ˜19hour. The mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was dissolved/suspended in DCM andfiltered through a silica pad and the filtrate was concentrated underreduced pressure. The residue was purified by column chromatography[SiO₂, 80 g, EtOAc/heptane] to provide vinylbiphenyl (1.845 g) as awhite solid. LCMS Rt 0.79 min.

Step 2: Preparation of (S)-tert-butyl1-(biphenyl-4-yl)-2-hydroxyethylcarbamate

To a solution of tert-butyl carbamate (2.82 g, 24.08 mmol) in 1-propanol(30 mL) was added aqueous NaOH solution (0.38M, 61.5 mL, 23.36 mmol).The mixture was stirred for 5 min and1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.351 g, 11.93 mmol)was added. The mixture was stirred for 10 min and (DHQ)₂PHAL (0.303 g,0.388 mmol), dissolved in 1-propanol (30 mL), was added followed by asolution of vinylbiphenyl (1.4 g, 7.77 mmol) in 1-propanol (60 mL). Asuspension of potassium osmate dihydrate (0.114 g, 0.311 mmol) inaqueous NaOH solution, (0.38M, 0.613 mL, 0.233 mmol) was added and themixture was stirred for ˜16 hours. The reaction mixture was diluted withwater (200 mL) and extracted with EtOAc (3×200 mL). The combined organiclayers were washed with brine (2×400 mL), dried over sodium sulfate,filtered off and concentrated under reduced pressure. The residue waspurified by column chromatography [SiO₂, 80 g, EtOAc/heptane] to provide(S)-tert-butyl 1-(biphenyl-4-yl)-2-hydroxyethylcarbamate (609 mg). LCMSm/z 258.2 (M+H; loss of t-Bu)⁺, Rt 0.97 min.

¹H NMR (400 MHz, CD₃OD) δ ppm 7.62-7.56 (m, 4H), 7.45-7.37 (m, 4H),7.34-7.2 (m, 1H), 4.69 (t, J=5.8 Hz, 1H), 3.76-3.63 (m, 2H), 1.44 (br.s., 9H)

Step 3: Preparation of (S)-2-amino-2-(biphenyl-4-yl)ethanol

To a solution of (S)-tert-butyl1-(biphenyl-4-yl)-2-hydroxyethylcarbamate (608 mg, 1.940 mmol) in MeOH(3 mL) was added HCl (4M in dioxane, 8 mL) at room temperature. Themixture was stirred for 1 hour and concentrated under reduced pressure.The residue was dissolved in DCM (10 mL)/water (1.0 mL) and stirred withNaHCO₃ for 1 hour. The mixture was filtered off and rinsed with DCM. Thefiltrate was dried over sodium sulfate, filtered off and concentratedunder reduced pressure providing (S)-2-amino-2-(biphenyl-4-yl)ethanol(171 mg) as a white solid. LCMS m/z 214.2 (M+H)⁺, Rt 0.58 min.

Step 4: Preparation of (S)-4-(biphenyl-4-yl)oxazolidin-2-one

To a solution of (S)-2-amino-2-(biphenyl-4-yl)ethanol (171 mg, 0.802mmol) in THF (12 mL) under argon atmosphere was added CDI (132 mg, 0.814mmol). The solution was stirred at room temperature for 2 hours. Themixture was diluted with saturated aqueous NaHCO₃ solution (40 mL) andextracted with EtOAc (2×30 mL). The combined organic layers were washedwith 0.5M aqueous HCl solution (30 mL), brine (40 mL), dried over sodiumsulfate, filtered off and concentrated under reduced pressure. Theresidue was dissolved in DCM and concentrated under reduced pressure toprovide crude (S)-4-(biphenyl-4-yl)oxazolidin-2-one (156 mg) as a beigesolid, which was used without further purification. LCMS m/z 240.1(M+H)⁺, Rt 0.80 min.

¹H NMR (400 MHz, CD₃OD) δ ppm 4.19 (dd, J=8.61, 6.50 Hz, 1H) 4.80 (t,J=8.73 Hz, 1H) 5.05 (dd, J=8.78, 6.48 Hz, 1H) 7.31-7.38 (m, 1H)7.39-7.54 (m, 4H) 7.55-7.71 (m, 4H).

Intermediate P 4,4,5,5-tetramethyloxazolidin-2-one

Step 1: Preparation of Methyl2-(tert-butoxycarbonylamino)-2-methylpropanoate

To a solution of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid(10.03 g, 49.4 mmol) in MeOH/DCM (60 mL/140 mL) at room temperature wasadded drop wise (trimethylsilyl)diazomethane (37.0 mL, 74.0 mmol). Thereaction mixture was stirred for 30 minutes. Acetic acid was added dropwise to quench (trimethylsilyl)diazomethane. The reaction mixture wasconcentrated under reduced pressure to afford the desired product as awhite solid (10.56 g). LCMS m/z 240.2 (M+Na)⁺, Rt 0.71 min.

Step 2: Preparation of tert-butyl3-hydroxy-2,3-dimethylbutan-2-ylcarbamate

To a solution of methyl 2-(tert-butoxycarbonylamino)-2-methylpropanoate(10.56 g, 48.6 mmol) in THF (300 mL) at 0° C. was added drop wisemethylmagnesium bromide (64.8 mL, 194 mmol). Cold bath was removed after1 hour. The reaction was stirred at 20° C. for 4 hours. The reaction wascooled back 0° C. and quenched with saturated NH₄Cl solution (10 mL).The reaction mixture was then allowed to warm to room temperature, anddiluted with EtOAc (100 mL) and water (50 mL). The phases were separatedand the aqueous layer was extracted with EtOAc (2×100 mL). The combinedorganics were then dried (Na₂SO₄) and concentrated. The residue waspurified via silica gel flash chromatography (0-20% EtOAc-Hexanes) toafford the desired product as a white solid (9.02 g). LCMS m/z 240.1(M+Na)⁺, Rt 0.78 min.

Step 3: Preparation of 4,4,5,5-tetramethyloxazolidin-2-one

To tert-butyl 3-hydroxy-2,3-dimethylbutan-2-ylcarbamate (10.02 g, 46.1mmol) in THF (300 ml) was added portion wise potassium2-methylpropan-2-olate (7.24 g, 64.6 mmol). The reaction was stirred forfive hours and quenched with HCl (1 M, 66 mL) to pH=2. The reactionmixture was then concentrated under vacuum to about one third of thevolume, and diluted with water (50 mL). The aqueous layer was thenextracted with DCM (3×100 mL). The combined organic was washed withbrine (50 mL), dried (Na₂SO₄) and concentrated to give crude product asa light tan oil (6.25 g). LCMS m/z 144.1 (M+H)⁺, Rt 0.42 min.

The Intermediates in Table 2b were prepared by a method similar to theone described for the preparation of Intermediate P.

TABLE 2b Intermediate: Name Structure LCMS Q: (4S)-4-isopropyl-5-methyloxazolidin-2-one

MS m/z (M + H)⁺ 144.4, Rt 0.47 min R: 4,4,5- trimethyloxazolidin-2- one

MS m/z (M + H)⁺ 130.4, Rt 0.36 min S: 4,4- dimethyloxazolidin-2- one

MS m/z (M + H)+ 116.0, Rt 0.28 min

Intermediate 1 (R)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one

A solution of (R)-4-phenyloxazolidin-2-one (2.9484 g, 18.07 mmol) and2,4-dichloropyrimidine (3.1872 g, 21.39 mmol, 1.184 equiv) in DMF (30mL) was treated with NaH (95%, 0.4773 g, 18.89 mmol, 1.046 equiv), thenthe resulting mixture (yellow to red cloudy) was stirred at roomtemperature for 3 h. The reaction mixture was diluted with EtOAc (200mL), washed with sat. NH₄Cl (75 mL) and 4% aqueous NaCl (2×100 mL),dried over Na₂SO₄, filtered and concentrated. Silica gel columnchromatography (EtOAc/Heptane 0 to 40%) provided(R)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one (2.7020 g, whitesticky solid) in 46.9% yield. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J=5.6Hz, 1H), 8.18 (d, J=6.1 Hz, 1H), 7.38-7.30 (m, 5H), 5.81 (dd, J=8.6, 3.5Hz, 1H), 4.88 (t, J=8.6 Hz, 1H), 4.37 (dd, J=8.6, 3.5 Hz, 1H); MS m/z276.4 (M+H)⁺.

The Intermediates in Table 3 were prepared by a method similar to theone described for the preparation of Intermediate 1.

TABLE 3

Intermediate 2 

Intermediate 3 

Intermediate 4 

Intermediate 5 

Intermediate 6 

Intermediate 7 

Intermediate 8 

Intermediate 9 

Intermediate 10

Intermediate 11

Intermediate 12

Intermediate 13

Intermediate 14

Intermediate 15

Intermediate 16

Intermediate 17

Intermediate 18

Intermediate 19

Intermediate 20

Intermediate 21

Intermediate 22

Intermediate 23

Intermediate 24

Intermediate 25

Intermediate 26

Intermediate 27

Intermediate 28

Intermediate 29

Intermediate 30

TABLE 4 Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 3. Intermediate: Name ¹H NMR (400 MHz) δppm LCMS 2: (S)-3-(2-chloropyrimidin-4- (CDCl₃) 8.47 (d, J = 6.1 Hz, 1H), 8.18 MS m/z yl)-4-phenyloxazolidin-2-one (d, J = 5.7 Hz, 1 H),7.39-7.29 (m, 5 276.5 (M + H), 5.81 (dd, J = 8.6, 3.5 Hz, 1 H), 4.88 H)⁺(t, J = 8.8 Hz, 1 H), 4.37 (dd, J = 8.8, 3.8 Hz, 1 H) 3:3-(2-chloropyrimidin-4- (CD₃OD) 8.48 (d, J = 6.1 Hz, 1 H), MS m/zyl)oxazolidin-2-one 8.16 (d, J = 6.1 Hz, 1 H), 4.54 (t, J = 200.4 (M +7.8 Hz, 2 H), 4.22 (t, J = 8.1 Hz, 2 H) H)⁺ 4: (S)-4-benzyl-3-(2-(CD₃OD) 8.52 (d, J = 6.1 Hz, 1 H), MS m/zchloropyrimidin-4-yl)oxazolidin- 8.15 (d, J = 6.1 Hz, 1 H), 7.32-7.22290.3 (M + 2-one (m, 5 H), 5.07-5.02 (m, 1 H), 4.46- H)⁺ 4.37 (m, 2 H),3.30-3.27 (m, 1 H), 3.06 (dd, J = 13, 8.1 Hz, 1 H) 5: (R)-4-benzyl-3-(2-(CD₃OD) 8.51 (d, J = 5.6 Hz, 1 H), MS m/zchloropyrimidin-4-yl)oxazolidin- 8.13 (d, J = 5.6 Hz, 1 H), 7.31-7.21290.3 (M + 2-one (m, 5 H), 5.06-4.98 (m, 1 H), 4.45- H)⁺ 4.34 (m, 2 H),3.30-3.25 (m, 1 H), 3.04 (dd, J = 14, 8.1 Hz, 1 H) 6:(S)-3-(2-chloropyrimidin-4- (CD₃OD) 8.50 (d, J = 5.9 Hz, 1 H), MS m/zyl)-4-isopropyloxazolidin-2-one 8.17 (d, J = 5.8 Hz, 1 H), 4.83-4.76242.6 (M + (m, 1 H), 4.48-4.43 (m, 2 H), 2.56 H)⁺ (dtd, J = 14, 7.0, 3.8Hz, 1 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.87 (d, J = 7.1 Hz, 3 H) 7:(S)-4-benzhydryl-3-(2- (CD₃OD) 8.41 (d, J = 5.8 Hz, 1 H), MS m/zchloropyrimidin-4-yl)oxazolidin- 8.01 (d, J = 5.8 Hz, 1 H), 7.35-7.26366.1 (M + 2-one (m, 3 H), 7.24-7.12 (m, 7 H), 5.86- H)⁺ 5.70 (m, 1 H),4.74 (d, J = 7.1 Hz, 1 H), 4.64 (t, J = 8.5 Hz, 1 H), 4.45 (dd, J = 9.1,2.0 Hz, 1 H) 8: (4R,5S)-3-(2- (CD₃OD) 8.52 (d, J = 6.1 Hz, 1 H), MS m/zchloropyrimidin-4-yl)-4-methyl- 8.20 (d, J = 6.1 Hz, 1 H), 7.48-7.38290.3 (M + 5-phenyloxazolidin-2-one (m, 5 H), 5.92 (d, J = 7.6 Hz, 1 H),5.15 H)⁺ (quin, J = 6.8 Hz, 1 H), 0.98 (d, J = 6.6 Hz, 3 H) 9:(4S,5R)-3-(2- (CD₃OD) 8.52 (d, J = 6.1 Hz, 1 H), MS m/zchloropyrimidin-4-yl)-4-methyl- 8.20 (d, J = 6.1 Hz, 1 H), 7.48-7.38290.3 (M + 5-phenyloxazolidin-2-one (m, 5 H), 5.92 (d, J = 7.6 Hz, 1 H),5.15 H)⁺ (quin, J = 6.7 Hz, 1 H), 0.98 (d, J = 6.6 Hz, 3 H) 10:(S)-3-(2-chloropyrimidin-4- (CD₃OD) 8.48 (d, J = 5.8 Hz, 1 H), MS m/zyl)-4-isopropyl-5,5- 8.20 (d, J = 5.8 Hz, 1 H), 4.63 (d, J = 270.1 (M +dimethyloxazolidin-2-one 3.1 Hz, 1 H), 2.29 (dtd, J = 14, 7.0, 3.1, H)⁺1 H), 1.60 (s, 3 H), 1.47 (s, 3 H), 1.05 (d, J = 7.1 Hz, 3 H), 0.99 (d,J = 7.1 Hz, 3 H) 11: (S)-3-(2-chloropyrimidin-4- (CD₃OD) 8.48 (d, J =5.8 Hz, 1 H), MS m/z yl)-5,5-dimethyl-4- 8.25 (d, J = 5.8 Hz, 1 H),7.39-7.30 304.3 (M + phenyloxazolidin-2-one (m, 3 H), 7.22 (br s, 2 H),1.67 (s, 3 H), H)⁺ 1.04 (s, 3 H) 12: (S)-3-(2-chloropyrimidin-4- (CD₃OD)8.49 (d, J = 5.9 Hz, 1 H), MS m/z yl)-4-isobutyloxazolidin-2-one 8.13(d, J = 5.9 Hz, 1 H), 4.83 (ddt, J = 256.3 (M + 10, 7.6, 2.9 Hz, 1 H),4.58-4.54 (m, 1 H)⁺ H), 4.31 (dd, J = 8.8, 2.8 Hz, 1 H), 1.87- 1.81 (m,1 H), 1.75-1.65 (m, 1 H), 1.62-1.55 (m, 1 H), 1.05 (d, J = 6.5 Hz, 3 H),0.99 (d, J = 6.5 Hz, 3 H) 13: (R)-3-(2-chloropyrimidin-4- (CD₃OD) 8.48(d, J = 5.8 Hz, 1 H), MS m/z yl)-4-isobutyloxazolidin-2-one 8.12 (d, J =6.0 Hz, 1 H), 4.87-4.79 256.3 (M + (m, 1 H), 4.57 (t, J = 8.6 Hz, 1 H),4.31 H)⁺ (dd, J = 8.6, 2.5 Hz, 1 H), 1.87-1.81 (m, 1 H), 1.75-1.65 (m, 1H), 1.62- 1.56 (m, 1 H), 1.05 (d, J = 6.6 Hz, 3 H), 0.99 (d, J = 6.6 Hz,3 H) 14: (S)-4-tert-butyl-3-(2- (CD₃OD) 8.50 (d, J = 5.9 Hz, 1 H), MSm/z chloropyrimidin-4-yl)oxazolidin- 8.12 (d, J = 5.9 Hz, 1 H), 4.94(dd, J = 256.4 (M + 2-one 7.6, 1.5 Hz, 1 H), 4.54 (dd, J = 9.1, 1.5 H)⁺Hz, 1 H), 4.46-4.42 (m, 1 H), 0.95 (s, 9 H) 15: (4R,5S)-3-(2- (CD₃OD)8.52 (d, J = 5.9 Hz, 1 H), MS m/z chloropyrimidin-4-yl)-4,5- 8.33 (d, J= 5.9 Hz, 1 H), 7.14-7.05 352.4 (M + diphenyloxazolidin-2-one (m, 8 H),6.93-6.91 (m, 2 H), 6.18- H)⁺ 6.11 (m, 2 H) 16: (4S,5R)-3-(2- (CD₃OD)8.52 (d, J = 5.9 Hz, 1 H), MS m/z chloropyrimidin-4-yl)-4,5- 8.33 (d, J= 5.9 Hz, 1 H), 7.14-7.05 352.3 (M + diphenyloxazolidin-2-one (m, 8 H),6.93-6.91 (m, 2 H), 6.18- H)⁺ 6.11 (m, 2 H) 17: (4S,5R)-3-(2- (CD₃OD)8.47 (d, J = 5.9 Hz, 1 H), MS m/z chloropyrimidin-4-yl)-5-methyl- 8.25(d, J = 5.9 Hz, 1 H), 7.40-7.31 290.4 (M + 4-phenyloxazolidin-2-one (m,3 H), 7.21 (d, J = 7.0 Hz, 2 H), 5.80 H)⁺ (d, J = 7.5 Hz, 1 H),5.18-5.12 (m, 1 H), 1.02 (d, J = 6.5 Hz, 3 H); 18: (S)-4-benzyl-3-(2-(CDCl₃) 8.45 (d, J = 5.8 Hz, 1 H), 8.16 MS m/zchloropyrimidin-4-yl)-5,5- (d, J = 5.8 Hz, 1 H), 7.37-7.28 (m, 4 318.1(M + dimethyloxazolidin-2-one H), 7.25-7.21 (m, 1 H), 4.87 (dd, J = H)⁺9.0, 4.5 Hz, 1 H), 3.24 (dd, J = 15, 4.5 Hz, 1 H), 2.97 (dd, J = 14, 9.0Hz, 1 H), 1.51 (s, 3 H), 1.45 (s, 3 H) 19: (S)-3-(2-chloropyrimidin-4-(CDCl₃) 8.76-8.75 (m, 1 H), 8.62 (d, J = MS m/zyl)-4-(pyridin-3-yl)oxazolidin-2- 3.5 Hz, 1 H), 8.47 (d, J = 5.8 Hz, 1277.4 (M + one H), 8.16 (d, J = 5.8 Hz, 1 H), 7.74 (dt, J = H)⁺ 8.0, 2.0Hz, 1 H), 7.35 (dd, J = 7.8, 4.8 Hz, 1 H), 5.83 (dd, J = 8.8, 3.8 Hz, 1H), 4.90 (t, J = 9.0 Hz, 1 H), 4.50 (dd, J = 9.0, 3.5 Hz, 1 H) 20:3-(2-chloropyrimidin-4-yl)- (CDCl₃) 8.44 (d, J = 5.8 Hz, 1 H), 8.25HRMS(B) 4-(4-methoxyphenyl)-5,5- (d, J = 5.8 Hz, 1 H), 7.13 (br d, J =7.0 m/z 334.0954 dimethyloxazolidin-2-one Hz, 2 H), 6.89 (d, J = 9.0 Hz,2 H), (M + H)⁺ 5.39 (s, 1 H), 3.82 (s, 3 H), 1.67 (s, 3 H), 1.11 (s, 3H) 21: (S)-3-(2-chloropyrimidin-4- (CDCl₃) 8.62-8.60 (m, 1 H), 8.45 (d,J = MS m/z yl)-4-(pyridin-2-yl)oxazolidin-2- 5.8 Hz, 1 H), 8.22 (d, J =5.8 Hz, 1 277.0 (M + one H), 7.73 (td, J = 7.7, 1.8 Hz, 1 H), 7.43 H)⁺(d, J = 7.5 Hz, 1 H), 7.29-7.26 (m, 1 H), 5.85 (dd, J = 8.5, 3.5 Hz, 1H), 4.82 (t, J = 8.8 Hz, 1 H), 4.64 (dd, J = 8.8, 3.8 Hz, 1 H) 22:(S)-3-(2-chloropyrimidin-4- (CDCl₃) 8.72-8.70 (m, 1 H), 8.52 (d, J = MSm/z yl)-4-(pyridin-4-yl)oxazolidin-2- 5.8 Hz, 1 H), 8.20 (d, J = 5.8 Hz,1 276.9 (M + one H), 7.43-7.42 (m, 1 H), 5.81 (dd, J = H)⁺ 8.8, 3.8 Hz,1 H), 4.91 (t, J = 9.0 Hz, 1 H), 4.44 (dd, J = 9.3, 3.8 Hz, 1 H) 23:(S)-3-(2-chloropyrimidin-4- (CDCl₃) 8.44 (d, J = 5.8 Hz, 1 H), 8.13 MSm/z yl)-4-methyl-4- (d, J = 5.8 Hz, 1 H), 7.41-7.28 (m, 5 289.9 (M +phenyloxazolidin-2-one H), 4.46 (d, J = 8.5 Hz, 1 H), 4.38 (d, J = H)⁺8.5 Hz, 1 H), 2.23 (s, 3 H) 24: (S)-3-(2-chloro-6- (CDCl₃) 8.06 (s, 1H), 4.83-4.77 (m, 1 MS m/z methylpyrimidin-4-yl)-4- H), 4.44-4.34 (m, 2H), 2.65-2.55 255.8 (M + isopropyloxazolidin-2-one (m, 1 H), 2.53 (s, 3H), 1.00 (d, J = 8 H)⁺ Hz, 3 H), 0.88 (d, J = 8 Hz, 3 H) 25:(S)-3-(2-chloro-5- (CDCl₃) 8.50 (s, 1 H), 5.01-4.96 (m, 1 MS m/zmethylpyrimidin-4-yl)-4- H), 4.53 (t, J = 9.0 Hz, 1 H), 4.28 (t, J =255.9 (M + isopropyloxazolidin-2-one 8.8 Hz, 1 H), 2.35 (s, 3 H), 2.16(td, J = H)⁺ 7.0 Hz, J = 4.5 Hz, 1 H), 0.93 (d, J = 7.0 Hz, 3 H), 0.84(d, J = 6.5 Hz, 3 H) 26: (S)-3-(2-chloro-5- (DMSO-d₆) 8.95 (d, J = 3.0Hz, 1 H), MS m/z fluoropyrimidin-4-yl)-4- 4.79-4.73 (m, 1 H), 4.58 (t, J= 9.0 259.9 (M + isopropyloxazolidin-2-one Hz, 1 H), 4.41 (dd, J = 8.5Hz, J = 6.5 H)⁺ Hz, 1 H), 2.24-2.16 (m, 1 H), 0.86 (d, J = 7.0 Hz, 3 H),0.78 (d, J = 6.5 Hz, 3 H) 27: (S)-3-(2,5- (DMSO-d₆) 9.01 (s, 1 H), 4.81(ddd, J = MS m/z dichloropyrimidin-4-yl)-4- 9.1 Hz, J = 7.8 Hz, J = 4.3Hz, 1 H), 274.2 (M − isopropyloxazolidin-2-one 4.59 (t, J = 8.8 Hz, 1H), 4.38-4.33 H)⁻ (m, 1H), 2.06 (td, J = 7.0 Hz, J = 4.3 Hz, 1 H), 0.84(d, J = 6.8 Hz, 3 H), 0.78 (d, J = 6.8 Hz, 3 H) 28:(R)-3-(2-chloropyrimidin-4- (CDCl₃) 8.20 (d, J = 5.8 Hz, 1 H), 8.01 MSm/z yl)-5,5-dimethyl-4- (d, J = 5.8 Hz, 1 H), 7.16-7.07 (m, 3 303.9 (M +phenyloxazolidin-2-one H), 6.98-6.96 (m, 2 H), 5.19 (s, 1 H), H)⁺ 1.46(s, 3 H), 0.87 (s, 3 H) 29: 3-(2-chloropyrimidin-4-yl)- (CDCl₃) 8.47 (d,J = 5.8 Hz, 1 H), 8.06 MS m/z 4,4-dimethyloxazolidin-2-one (d, J = 5.8Hz, 1 H), 4.17 (s, 2 H), 1.77 228.3 (M + (s, 6 H) H)⁺ 30:(R)-3-(2-chloropyrimidin-4- (CDCl₃) 8.43 (d, J = 5.8 Hz, 1 H), 8.13 MSm/z yl)-4-methyl-4- (d, J = 5.8 Hz, 1 H), 7.40-7.36 (m, 4 289.9 (M +phenyloxazolidin-2-one H), 7.35-7.28 (m, 1 H), 4.45 (d, J = H)⁺ 8.6 Hz,1 H), 4.38 (d, J = 8.6 Hz, 1 H), 2.22 (s, 3 H)

Intermediate 31(S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one

A solution of 2,4-difluoropyrimidine (3.5 mL, 41 mmol) and(S)-4-isopropyloxazolidin-2-one (5.3 g 41 mmol) in 30 mL DMF was cooledto 0° C. under N₂ atmosphere. NaH (2.1 g of 60% suspension, 53 mmol) wasslowly added. Bubbling exotherm observed. Internal temp was kept below5° C. After 5 minutes, cold bath was removed. Reaction mixture (a sandysuspension) was allowed to warm to room temp and stir 18 h. The reactionmixture was diluted with water (100 mL) and extracted with (3×75 mL)EtOAc. Organic layer was washed with 50 mL each water, and brine. Driedover Na₂SO₄, and concentrated on silica gel in vacuo. Columnchromatography (EtOAc/heptane 10 to 100% gradient) gave 3.1 g(S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (IV) as acrystalline white solid (33%). ¹H NMR (400 MHz, CDCl₃) δ 8.50 (dd,J=5.8, 2.2 Hz, 1H), 8.19 (dd, J=5.8, 3.8 Hz, 1H), 4.79 (dt, J=8.1, 3.5Hz, 1H), 4.48-4.34 (m, 2H), 2.64 (heptd, J=7.0, 3.6 Hz, 1H), 1.01 (d,J=7.0 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H). MS m/z 471.8 and 471.8 (M+H)+.

The Intermediates in Table 4b were prepared by a method similar to theone described for the preparation of Intermediate 1 and 31.

TABLE 4b

Intermediate 32

Intermediate 33

Intermediate 34

Intermediate 35

Intermediate 36

Intermediate 37

Intermediate 38

Intermediate 39

Intermediate 40

Intermediate 41

Intermediate 42

Intermediate 43

Intermediate 44

TABLE 4c Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 4b. Intermediate: Name ¹H NMR (400 MHz) δppm LCMS 32: 3-(2-fluoropyrimidin-4- (CDCl₃) 8.51 (dd, J = 5.8, 2.0 Hz,1 H), MS m/z yl)oxazolidin-2-one 8.17 (dd, J = 5.8, 2.0 Hz, 1 H), 4.61-184.0 (M + 4.57 (m, 2 H), 4.31-4.27 (m, 2 H) H) 33:(R)-3-(2-chloropyrimidin-4- (CDCl₃) 8.45 (d, J = 5.8 Hz, 1 H), 8.12 MSm/z yl)-4-(4-fluorophenyl)-4- (d, J = 5.8 Hz, 1 H), 7.40-7.35 (m, 2308.0 (M + methyloxazolidin-2-one H), 7.10-7.04 (m, 2 H), 4.40-4.37 H)+(m, 2 H), 2.22 (s, 3 H) 34: 1-(2-chloropyrimidin-4-yl)- (CDCl₃) 8.48 (d,J = 5.8 Hz, 1 H), 8.12 MS m/z 3-oxa-1-azaspiro[4.4]nonan-2- (d, J = 5.8Hz, 1 H), 4.22 (s, 2 H), 2.66- 254.1 (M + one 2.59 (m, 2 H), 2.22-2.14(m, 2 H), H)+ 1.75-1.62 (m, 4 H) 35: (4S)-3-(2-chloropyrimidin-4- MS m/z(M + yl)-4-isopropyl-5- H)+ 256.2, Rt methyloxazolidin-2-one 0.87 min36: (4S)-3-(2-chloro-5- MS m/z (M + fluoropyrimidin-4-yl)-4- H)+ 274.1,Rt isopropyl-5-methyloxazolidin-2- 0.82 min one 37:3-(2-chloropyrimidin-4-yl)- MS m/z (M + 4,4,5,5-tetramethyloxazolidin-H)+ 256.1, Rt 2-one 0.85 min 38: 3-(2-chloro-5- MS m/z (M +fluoropyrimidin-4-yl)-4,4,5,5- H)+ 274.1, Rt tetramethyloxazolidin-2-one0.83 min 39: 3-(2-chloropyrimidin-4-yl)- MS m/z (M +4,4,5-trimethyloxazolidin-2-one H)+ 242.1, Rt 0.81 min 40:3-(2-chloro-5- MS m/z (M + fluoropyrimidin-4-yl)-4,4,5- H)+ 260.1, Rttrimethyloxazolidin-2-one 0.77 min 41: 1-(2-chloro-5- (CDCl₃) 8.47 (d, J= 2 Hz, 1 H), 4.28 MS m/z (M + fluoropyrimidin-4-yl)-3-oxa-1- (s, 2 H),2.54-2.44 (m, 2 H), 2.11- H)+ 272.4 azaspiro[4.4]nonan-2-one 1.99 (m, 2H), 1.90-1.82 (m, 2 H), 1.72-1.61 (m, 42 H) 42:3-(2-chloropyrimidin-4-yl)- MS m/z (M + 4,4-dimethyloxazolidin-2-one H)+228.0, Rt 0.73 min 43: 3-(2-chloro-5- MS m/z (M +fluoropyrimidin-4-yl)-4,4- H)+ 246.0, Rt dimethyloxazolidin-2-one 0.70min 44: 3-(2-chloro-5- MS m/z (M + fluoropyrimidin-4-yl)oxazolidin- H)+218.0, Rt 2-one 0.47 min

Intermediate 46(S)-4-(biphenyl-4-yl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one

To a solution of 2,4-dichloropyrimidine (46.5 mg, 0.312 mmol) and(S)-4-(biphenyl-4-yl)oxazolidin-2-one (74.7 mg, 0.312 mmol) in DMF (700μL) was added NaH (60% wt., 10.49 mg, 0.437 mmol) in two portions within˜5 min [Caution: exotherm; gas development] at room temperature (waterbath). The reaction mixture was stirred for 1.5 hour. The mixture wasdiluted with EtOAc (25 mL), stirred for 5 min and then diluted slowlywith diluted brine (10 mL; 1:1 brine/water). The mixture was poured intodiluted brine (40 mL) and EtOAc (25 mL). The separated organic phase waswashed with diluted brine (3×40 ml), dried over Na₂SO₄, filtered off andconcentrated under reduced pressure. The residue was purified by columnchromatography [SiO₂, 40 g, EtOAc/heptane] to provide(S)-4-(biphenyl-4-yl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (49.5mg). LCMS m/z 352.2 (M+H)⁺, Rt 1.06 min.

Intermediate 473-(2-chloropyrimidin-4-yl)-4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one

To a mixture of 4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one (300 mg,1.286 mmol) and 2,4-dichloropyrimidine (192 mg, 1.286 mmol) in DMF (7mL) under argon was added NaH (60% wt., 67.9 mg, 2.83 mmol) in twoportions. The mixture was stirred for ˜1 hour. The reaction mixture wascarefully poured into ice-coiled 0.25N aqueous HCl solution. DCM andaqueous NaHCO₃ solution were added. The separated aqueous layer wasextracted with DCM (3×) and ethyl acetate (1×). The organic layers (DCMand ethyl acetate containing layers independently) were washed withbrine, dried over Na₂SO₄ and filtered off. The organic layers werecombined and concentrated under reduced pressure providing crude3-(2-chloropyrimidin-4-yl)-4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one(330 mg) as a yellowish liquid, which was directly used in the nextreaction without further purification. LCMS m/z 346.1 (M+H)⁺, Rt 0.83min.

Intermediate 487-(2-chloropyrimidin-4-yl)-8-phenyl-2,5-dioxa-7-azaspiro[3.4]octan-6-one

Prepared using similar methods as described above for3-(2-chloropyrimidin-4-yl)-4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one,but starting with oxetan-3-one. LCMS m/z 318.1 (M+H)⁺, Rt 0.78 min.

Intermediate 503-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloxazolidin-2-one

Step 1

A solution of 2,4-dichloro-5-fluoropyrimidine (2 g, 11.98 mmol) inacetonitrile (10 mL) was cooled to −40° C., avoiding freezing. To thissolution was added diisopropylamine (3.82 mL, 21.88 mmol) followed by1-amino-2-methylpropan-2-ol (1.5 g, 16.83 mmol). The reaction mixturewas removed from the cooling bath, warmed to room temperature andallowed to stir overnight (˜18 hours). Solvents were removed in vacuoand the residue was taken up in a minimum of dichloromethane (˜1.5-2 mL)and diluted with heptane until slightly cloudy. This mixture was loadedonto a 40 gram BioRad silica gel cartridge. Purification by flashchromatography (Analogix System, 20 min gradient, 0-25%methanol/dichloromethane, 40 mL/min.) provided1-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropan-2-ol as a whitesolid. LCMS m/z 220.1, 221.8 (M+H)⁺, Rt 0.49 min.

Step 2

To a suspension of1-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropan-2-ol (400 mg,1.82) in DCM/ethylacetate (5 mL) was added 2,6-lutidine (1 mL, 8.59mmol). The reaction was cooled to −78° C. and triphosgene (292 mg, 0.983mmol) was added in a single portion. The reaction was removed from thecooling bath and allowed to warm to room temperature. The reaction had apinkish coloration at this time. LCMS indicated consumption of startingmaterial and conversion the intermediate acyl chloroformate adduct of1-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropan-2-ol. Thereaction was sealed and stirred overnight. The reaction was stirred atroom temperature overnight to provide only partial closure of theintermediate acyl formate to the cyclic carbamate. The reaction (sealed)was then heated at 60° C. for ˜4 hours until intermediate acylchloroformate was consumed. Reaction was cooled to room temperature,diluted with DCM (˜50 mL) and washed with water (1×50 mL) and sat.NaHCO₃ (1×50 mL). Aqueous layers were back extracted with DCM (˜50 mL).The combined organics were dried over MgSO₄, filtered and concentratedin vacuo. The solid was dissolved in DCM (˜15 mL) and celite (˜4 gram)was added. The mixture was concentrated and dried in vacuo to provide asolid pre-load for subsequent purification. Purification by flashchromatography (Analogix System, 80 gram silica gel column, 25 min.gradient, 0-25% methanol/dichloromethane, 40 mL/min) provided3-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloxazolidin-2-one as awhite solid. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 1.58 (s, 8H) 4.02 (s,2H) 8.59 (d, J=3.13 Hz, 1H): LCMS m/z (M+H)⁺246.1, 247.8.0, Rt 0.61 min

The Intermediates in Table 4d were prepared by methods similar to theone described for the preparation of Intermediate 50.

TABLE 4d

Intermediate 51

Intermediate 52

TABLE 4e Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 4d. ¹H NMR (400 MHz, METHANOL-d4) δIntermediate: Name ppm LCMS 51: 3-(2-chloro-5-fluoropyrimidin- 1.52 (d,J = 6.26 Hz, 3 H) 3.89 (dd, MS m/z (M + 4-yl)-5-methyloxazolidin-2-one J= 9.78, 7.43 Hz, 1 H) 4.26 (dd, J = 9.78, H)⁺ 232.0, 7.43 Hz, 1 H)4.90-4.98 (m, 1 H) 8.58 233.9, Rt (d, J = 2.74 Hz, 1 H) 0.52 min 52:6-(2-chloro-5-fluoropyrimidin- 0.90-1.08 (m, 2 H) 1.18-1.37 (m, 2 MS m/z(M + 4-yl)-4-oxa-6-azaspiro[2.4]heptan- H) 4.31 (s, 2 H) 8.61 (d, J =3.13 Hz, 1 H)⁺ 244.0, 5-one H) 245.8, Rt 0.61 min

Intermediate 533-(2,6-dichloropyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one

A solution of 4,4-dimethyloxazolidin-2-one (0.103 g, 0.895 mmol) and2,4,6-trichloropyrimidine (0.181 g, 0.984 mmol, 1.10 equiv) in DMF (3mL) was treated with NaH (60%, 0.0429 g, 1.07 mmol, 1.2 equiv), then theresulting mixture (yellow) was stirred at room temperature for 1 h. Thereaction mixture was diluted with EtOAc (20 mL), washed with saturatedaqueous NaCl (2×20 mL), dried over Na₂SO₄, filtered and concentrated.Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided3-(2,6-dichloropyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one (0.146 g,white solid) in 62.3% yield. ¹H NMR (300 MHz, CDCl₃) δ 8.14 (s, 1H),4.16 (s, 2H), 1.74 (s, 9H); LCMS m/z 261.9 (M+H)⁺, Rt 0.91 min.

The Intermediates in Table 4f were prepared by a method similar to theone described for the preparation of Intermediate 53.

TABLE 4f

Intermediate 54

Intermediate 55

TABLE 4g Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 4f. Intermediate: Name ¹H NMR (400 MHz) δppm LCMS 54: 3-(2,6-dichloropyrimidin-4- (CDCl₃) 8.20 (s, 1 H), 4.59 (t,J = 8.0 MS m/z yl)oxazolidin-2-one Hz, 2 H), 4.29 (t J = 8.0 Hz, 2 H)234.0 (M + H)⁺, Rt 0.67 min 55: 3-(2,6-difluoropyrimidin-4- (CDCl₃) 7.68(d, J = 2.0 Hz, 1 H), 4.16 MS m/z yl)-4,4-dimethyloxazolidin- (s, 2 H),1.74 (s, 6 H) 230.1 (M + 2-one H)⁺, Rt 0.79 min

Intermediate 56 (S)-methyl 4-(1-(tert-butoxycarbonylamino)ethyl)benzoate

To a solution of (S)-methyl 4-(1-aminoethyl)benzoate (4.9 g, 22.7 mmol)in DCM (114 mL) was added di-tert-butyl dicarbonate (5.95 g, 27.3 mmol)and triethylamine (6.97 mL, 50 mmol). The solution was stirred for 16 hat room temperature then washed with water and brine. The organic layerwas dried over Na₂SO₄, filtered and concentrated. Silica gel columnchromatography (EtOAc/heptane 0 to 80%) provided (S)-methyl4-(1-(tert-butoxycarbonylamino)ethyl)benzoate as a white solid (6.35 g,100% yield).

¹H NMR (400 MHz, CDCl₃) δ 8.04-7.96 (m, 2H), 7.40-7.33 (m, 2H), 4.83 (s,1H), 3.91 (s, 3H), 1.43-1.23 (m, 12H); MS m/z 224.0 (M−56+H).

Intermediate 57 (S)-tert-butyl 1-(4-(hydroxymethyl)phenyl)ethylcarbamate

To a cooled (0° C.) solution of (S)-methyl4-(1-(tert-butoxycarbonylamino)ethyl)benzoate (6.35 g, 22.7 mmol) in THF(114 mL) was added a solution of LAH in THF (2.0 M, 13.64 mL, 27.3 mmol)and the resulting mixture was stirred at room temperature for 40 min.The reaction mixture was quenched by addition of a 1N NaOH solutionuntil gas evolution ceased. The reaction mixture was filtered, washedwith EtOAc. After separation, the aqueous phase was washed with EtOAc(2×150 mL). Combined organics were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/heptane 0 to 100%)provided (S)-tert-butyl 1-(4-(hydroxymethyl)phenyl)ethylcarbamate as awhite solid (5.01 g, 84% yield).

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.23 (m, 4H), 4.80-4.71 (m, 1H), 4.67 (s,2H), 2.04 (bs, 1H), 1.47-1.37 (m, 12H); MS m/z 196.0 (M−56+H).

Intermediate 58 (S)-tert-butyl 1-(4-(chloromethyl)phenyl)ethylcarbamate

To a solution of (S)-tert-butyl1-(4-(hydroxymethyl)phenyl)ethylcarbamate (503 mg, 2 mmol) in DCM (10mL) was added methanesulfonyl chloride (275 mg, 2.4 mmol) andtriethylamine (0.56 mL, 4 mmol). The solution was stirred for 16 h atroom temperature then washed with water and brine. After separation, theorganic phase was dried over Na₂SO₄, filtered and concentrated. Silicagel column chromatography (EtOAc/heptane 0 to 80%) provided(S)-tert-butyl 1-(4-(chloromethyl)phenyl)ethylcarbamate as a white solid(254 g, 47.1% yield).

¹H NMR (400 MHz, CDCl₃) δ 7.40-7.24 (m, 4H), 4.79 (s, 1H), 4.58 (s, 2H),1.50-1.30 (br m, 12H); MS m/z 214.0 (M−56+H).

Intermediate 59 (S)-tert-butyl1-(4-((5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)phenyl)ethylcarbamate

A solution of (S)-tert-butyl 1-(4-(chloromethyl)phenyl)ethylcarbamate(127 mg, 0.47 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine(91 mg, 0.56 mmol) and DIPEA (183 mg, 1.41 mmol) in DMSO (2.3 mL) washeated at 80° C. for 16 h. The reaction mixture was diluted with EtOAc(20 mL) and washed with water (20 mL). After separation, the aqueousphase was washed with EtOAc (2×15 mL). Combined organics were dried overNa₂SO₄, filtered and concentrated. The crude product was used to nextstep without further purification.

MS m/z 358.3 (M+H)

Intermediate 60(S)-1-(4-((5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)phenyl)ethanamine

To a solution of (S)-tert-butyl1-(4-((5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)phenyl)ethylcarbamate(168 mg, 0.47 mmol) in DCM (2 mL) was added TFA (2 mL, 26 mmol) slowlyat −78° C. The reaction was stirred at room temperature for 1 h thenconcentrated and diluted with DCM (10 mL). The solution was stirred with3 eq. of MP-carbonate resin (3.28 mmol/g, Biotage) for 1 hour at roomtemperature. The resin was removed by filtration and washed (2×5 mL)with DCM. The filtrate was concentrated and the crude residue was usedto next step without further purification.

MS m/z 258.2 (M+H).

Intermediate 61(S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoic acid

To a solution of (S)-4-(1-aminoethyl)-2-fluorobenzoic acid (5 g, 22.76mmol) in water (66 mL) and THF (66 mL) was added di-tert-butyldicarbonate (6.95 g, 31.9 mmol) and sodium carbonate (5.74 g, 68.3mmol). The solution was stirred for 16 h at room temperature then THFwas removed under reduced pressure. The aqueous solution was acidifiedwith 1N HCl to pH 3-4 and extracted with EtOAc (3×60 mL). Combinedorganics were dried over Na₂SO₄, filtered and concentrated to give awhite solid (1.94 g, 30.1% yield). The crude product was used to nextstep without further purification.

¹H NMR (400 MHz, MeOD) δ 7.89 (t, J=7.8 Hz, 1H), 7.20 (dd, J=8.2, 1.7Hz, 1H), 7.13 (dd, J=12.0, 1.6 Hz, 1H), 4.70 (d, J=7.1 Hz, 1H),1.47-1.35 (m, 12H); MS m/z 282.0 (M−H).

Intermediate 62 (S)-tert-butyl1-(3-fluoro-4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate

A solution of (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoicacid (1.416 g, 5 mmol), N,O-dimethylhydroxylamine hydrochloride (732 mg,7.5 mmol), HATU (2.85 g, 7.5 mmol) and DIPEA (3.49 mL, 20 mmol) in DMF(25 mL) was stirred at room temperature for 16 h. The reaction mixturewas diluted with EtOAc and washed with water. After separation, theaqueous phase was washed with EtOAc (2×75 mL). Combined organics weredried over Na₂SO₄, filtered and concentrated. Silica gel columnchromatography (EtOAc/heptane 12 to 100%) provided (S)-tert-butyl1-(3-fluoro-4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate as a whitesolid (1.5 g, 92% yield).

¹H NMR (400 MHz, CDCl₃) δ 7.40 (t, J=7.4 Hz, 1H), 7.13 (dd, J=7.8, 1.6Hz, 1H), 7.04 (dd, J=10.7, 1.6 Hz, 1H), 4.80 (br s, 1H), 3.56 (s, 3H),3.34 (s, 3H), 1.50-1.29 (m, 12H); MS m/z 327.1 (M+H).

Intermediate 63 (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate

Procedure 1: To a cooled (0° C.) solution of (S)-tert-butyl1-(3-fluoro-4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate (1.175 g,3.6 mmol) in THF (36 mL) was added a solution of LAH in THF (1.0 M, 18mL, 18 mmol) and the resulting mixture was stirred at 0° C. for 20 min.The reaction mixture was quenched by addition of a saturated Na₂SO₄solution until gas evolution ceased. The reaction mixture was extractedwith EtOAc (2×100 mL). Combined organics were dried over Na₂SO₄,filtered and concentrated. Silica gel column chromatography(EtOAc/heptane 12 to 100%) provided (S)-tert-butyl1-(3-fluoro-4-formylphenyl)ethylcarbamate as a white solid (760 mg, 79%yield).

Procedure 2: A solution of (S)-tert-butyl1-(4-bromo-3-fluorophenyl)ethylcarbamate (318 mg, 1 mmol) in dry THF (5mL) was cooled to −78° C. BuLi (2.5 M, 840 μL, 2.1 mmol) was addeddropwise and the resulting solution was stirred at −78° C. for 1 h. ThenDMF (232 μL, 3.00 mmol) was added in one portion. The reaction wasstirred for another 30 min at −78° C. then quenched with sat. NH4Clsolution. The reaction was stirred at room temperature for another 30min then diluted with EtOAc, washed with water and brine. The separatedorganic was dried over Na₂SO₄, filtered and concentrated. Silica gelcolumn chromatography (EtOAc/heptane 0 to 80%) provided (S)-tert-butyl1-(3-fluoro-4-formylphenyl)ethylcarbamate as a white solid (70 mg, 26.2%yield).

¹H NMR (400 MHz, CDCl₃) δ 10.31 (s, 1H), 7.87-7.80 (m, 1H), 7.20 (dd,J=8.2, 1.3 Hz, 1H), 7.11 (dd, J=11.5, 1.4 Hz, 1H), 4.80 (br s, 1H), 1.45(br s, 12H); MS m/z 212.1 (M−56+H).

Intermediate 64 (S)-tert-butyl1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethylcarbamate

(General Procedure A for Reductive Amination)

A solution of (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate(267 mg, 1 mmol) and 1,2,2-trimethylpiperazine dihydrochloride (402 mg,2 mmol) in THF (5 mL) was stirred at room temperature for 1 h andtreated with sodium triacetoxyborohydride (848 mg, 4 mmol). Theresulting mixture was stirred at room temperature for 16 h. The reactionmixture was quenched with saturated aqueous solution of NaHCO₃ (15 mL)and extracted with EtOAc (3×25 mL). Combined organics were dried overNa₂SO₄, filtered and concentrated. Silica gel column chromatography(MeOH/CH₂Cl₂ 0 to 10%) provided (S)-tert-butyl1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethylcarbamateas a white solid (186 mg, 49% yield).

¹H NMR (400 MHz, CDCl₃) δ 7.35 (t, J=7.7 Hz, 1H), 7.03 (dd, J=7.9, 1.9Hz, 1H), 6.95 (dd, J=11.1, 1.8 Hz, 1H), 4.77 (s, 1H), 3.49 (s, 2H), 2.56(br s, 4H), 2.24 (br s, 5H), 1.42 (br s, 12H), 1.04 (s, 6H); MS m/z380.4 (M+H).

Intermediate 65 tert-butyl(1S)-1-(4-((3,4-dimethylpiperazin-1-yl)methyl)phenyl)ethylcarbamate

A solution of (S)-tert-butyl 1-(4-formylphenyl)ethylcarbamate (84.1 mg,0.337 mmol) [obtained from (S)-1-(4-bromophenyl)ethanamine following theprocedure of Hashihayata, Takashi PCT Int. Appl., 2008081910, 10 Jul.2008] and 1,2-dimethylpiperazine (86.3 mg, 0.756 mmol, 2.24 equiv) inTHF (1.5 mL) was stirred at room temperature for 65 min and treated withsodium triacetoxyborohydride (277.2 mg, 1.308 mmol, 3.88 equiv). Theresulting mixture was stirred at room temperature for 16 hours. Thereaction mixture was quenched with saturated aqueous solution of NaHCO₃(15 mL) and extracted with EtOAc (5×15 mL). Combined organics were driedover Na₂SO₄, filtered and concentrated. Silica gel column chromatography(MeOH/CH₂Cl₂ 0 to 20%) provided tert-butyl(1S)-1-(4-((3,4-dimethylpiperazin-1-yl)methyl)phenyl)ethyl carbamate(90.7 mg) in 34.5% yield.

¹H NMR (400 MHz, CD₃OD) δ 7.29 (s, 4H), 4.68 (br s, 1H), 3.54-3.47 (m,2H), 3.37 (s, 1H), 2.84-2.74 (m, 3H), 2.38 (td, J=12, 2.5 Hz, 1H), 2.31(s, 3H), 2.28-2.22 (m, 2H), 1.94-1.89 (m, 1H), 1.40 (br s, 9H), 1.38 (d,J=6.9 Hz, 3H), 1.06 (d, J=6.3 Hz, 3H); MS m/z 348.2 (M+H)

Intermediate 66(R,E)-2-methyl-N-((3-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide

3-methyl-1H-pyrazole-4-carbaldehyde (2.03 g, 18.44 mmol) was dissolvedin THF (30 ml) and (R)-2-methylpropane-2-sulfinamide (2.35, 19.39 mmol)was added followed by Ti(OEt)4 (8.41 mmol, 36.90 mmol). The resultingreaction mixture was stirred at 80° C. for 18 h. LCMS shows mostlyproduct. The reaction mixture was diluted with EtOAc (300 mL), washedwith 4% aqueous NaCl (2×150, 2×50 mL). The combined aq. layers were backextracted with EtOAc (100 ml). The combined organic layers were washedwith brine (100 ml), dried over Na₂SO₄, filtered and concentrated.Purified by column chromatography (REDI 80 g, EtOAc/heptane 20-100% over33 min 100% for 7 min.) to give title compound (2.25 g, 10.55 mmol).

¹H NMR (400 MHz, MeOD) δ 8.55 (s, 1H), 2.53 (s, 3H), 1.25 (s, 9H). MS214.2 m/z (M+H)

Intermediate 67(R)-2-methyl-N—((S)-1-(3-methyl-1H-pyrazol-4-yl)ethyl)propane-2-sulfinamide

(R,E)-2-methyl-N-((3-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide(2.25 g, 10.55 mmol) was dissolved in THF and cooled to 0 C.Methylmagnesium bromide (3M, 12.5 ml, 37.5 mmol) was added dropwise andthe resulting solution was stirred for 1 h. Ice bath was removed and thereaction was stirred for another 15 h. Another 2.5 eq. ofmethylmagnesium bromide MeMgBr was added (at 0° C.). Not a lot of changeby LCMS.

The reaction mixture was quenched with sat NH4Cl and the aq. layer waswashed with THF (2×). Combined organic layers washed with brine, driedover Na₂SO₄, filtered and concentrated to give title compound (1.79 g,7.80 mmol)

¹H NMR (400 MHz, MeOD) δ 7.48 (s, 1H), 4.49 (qd, J=6.7, 4.7 Hz, 1H),2.26 (s, 3H), 1.57 (dd, J=6.5, 1.3 Hz, 3H), 1.23 (s, 9H). MS 230.2 m/z(M+H)

Intermediate 68(R)—N—((S)-1-(1-benzyl-3-methyl-1H-pyrazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide

(R)-2-methyl-N—((S)-1-(3-methyl-1H-pyrazol-4-yl)ethyl)propane-2-sulfinamide(290 mg, 1.26 mmol) was dissolved in DMF (5 ml) and added dropwise to asolution of Cs2CO3 (458 mg, 1.41 mmol) in DMF (4 ml). The resultingreaction mixture was stirred at room temperature for 15 min.benzylbromide (216 mg, 1.26 mmol) was added and the reaction was stirredat room temperature for 2 h. LCMS shows mostly product with somestarting pyrazole. Added another 0.1 ml of BnBr and 135 mg of Cs₂CO₃.Stirred another 24H at 50° C. The reaction mixture was diluted withEtOAc (300 mL), washed with 4% aqueous NaCl (2×150, 2×50 mL). Thecombined aq. layers were back extracted with EtOAc (100 ml). Thecombined organic layers were washed with brine (100 ml), dried overNa₂SO₄, filtered and concentrated. Silica gel chromatography,EtOAc/heptane 20-80% to give title compound (mix of regioisomers, 150mg, 0.470 mmol).

¹H NMR (400 MHz, MeOD) δ 7.54 (s, 0.6H), 7.46 (s, 0.4H), 7.36-6.99 (m,5H), 5.31 (s, 0.8H), 5.21 (s, 1.2H), 4.44 (t, J=6.9 Hz, 1H), 2.21 (2s,3H), 1.54 (2 dt, 3H), 1.17 (s, 9H). MS 320.2 m/z (M+H)

Intermediate 69 (S)-1-(1-benzyl-3-methyl-1H-pyrazol-4-yl)ethanaminehydrochloride

(R)—N—((S)-1-(1-benzyl-3-methyl-1H-pyrazol-4-yl)ethyl)-2-methylpropane-2-sulfinamidewas dissolved in dioxane (5 ml) and 4N HCl in dioxane (1.2 ml, 10 eq.)was added. Stirred 1H at room temperature. The solvents were removed andco-yapped twice with CH₂Cl₂. Some t-butyl observed by NMR. Resubmittedto reaction conditions and work-up to give title compound.

¹H NMR mixture of regioisomers (400 MHz, MeOD) δ 8.00 (s, 0.7H), 7.80(s, 0.3H), 7.52-6.96 (m, 5H), 5.40 (s, 0.6H), 5.36 (s, 1.4H), 4.47 (q,J=6.9 Hz, 1H), 2.34 (s, 2.1H), 2.32 (s, 0.9H), 1.62 (2d, J=6.9 Hz, 3H).

MS 216.3 m/z (M+H)

The Intermediates in Table 4h were prepared by methods substantiallysimilar to those described for the preparation of Intermediates 56through 69.

TABLE 4h

Intermediate 70

Intermediate 71

Intermediate 72

Intermediate 73

Intermediate 74

Intermediate 75

Intermediate 76

Intermediate 77

Intermediate 78

Intermediate 79

Intermediate 80

Intermediate 81

Intermediate 82

Intermediate 83

Intermediate 84

Intermediate 85

Intermediate 86

Intermediate 87

Intermediate 88

Intermediate 89

Intermediate 90

Intermediate 91

Intermediate 92

Intermediate 93

Intermediate 94

Intermediate 95

Intermediate 96

Intermediate 97

Intermediate 98

Intermediate 99

 Intermediate 100

Intermediate 101

Intermediate 102

Intermediate 103

Intermediate 104

Intermediate 105

Intermediate 106

Intermediate 107

Intermediate 108

Intermediate 109

Intermediate 110

 Intermediate 111

 Intermediate 112

 Intermediate 113

 Intermediate 114

 Intermediate 115

 Intermediate 116

 Intermediate 117

 Intermediate 118

 Intermediate 119

 Intermediate 120

 Intermediate 121

 Intermediate 122

 Intermediate 123

 Intermediate 124

 Intermediate 125

TABLE 4i Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 4h. Intermediate: Name ¹H NMR (400 MHz) δppm LCMS 70: (S)-1-(3-fluoro-4-((3,3,4- MS m/z trimethylpiperazin-1-280.2 (M + H). yl)methyl)phenyl)ethanamine 71: (S)-tert-butyl1-(4-bromo-3- (CDCl₃) 7.51-7.45 (m, 1H), MS m/zfluorophenyl)ethylcarbamate 7.07 (dd, J = 9.8, 2.0 Hz, 1H), 317.9 (M +H). 6.98 (dd, J = 8.4, 2.1 Hz, 1H), 4.67 (br s, 1H),, 1.41(br s, 12H)72: (S)-tert-butyl 1-(3-fluoro-4-((4- (CDCl₃) 7.28 (t, J = 7.7 Hz, 1H),MS m/z methylpiperazin-1- 7.01 (dd, J = 7.7, 1.8 Hz, 1H), 353.2 (M + H)yl)methyl)phenyl)ethylcarbamate 6.94 (dd, J = 10.8, 1.9 Hz, 1H), 4.86(br s, 1H), 4.74 (br s, 1H), 3.54 (s, 2H), 2.67-2.29 (m, 8H), 2.25 (s,3H), 1.51-1.26 (m, 12H) 73: (S)-1-(3-fluoro-4-((4- MS m/zmethylpiperazin-1- 252.1 (M + H) yl)methyl)phenyl)ethanamine 74:(S)-benzyl 4-(4-(1-(tert- (CDCl₃) 7.43-7.19 (m, 9H), MS m/zbutoxycarbonylamino) 5.12 (s, 2H), 4.78 (br s, 2H), 454.3 (M + H)ethyl)benzyl)piperazine-1- 3.95-3.20 (m, 6H), 2.43 (br s, carboxylate4H), 1.43 (br s, 12H) 75: (S)-benzyl 4-(4-(1- MS m/zaminoethyl)benzyl)piperazine-1- 354.3 (M + H) carboxylate 76:(1S)-1-(4-((3,5- MS m/z dimethylpiperazin-1- 248.2 (M + H)yl)methyl)phenyl)ethanamine 77: (S)-tert-butyl 1-(4-((4-methyl-1,4-(CDCl₃) 7.31-7.20 (m, 4H), MS m/z diazepan-1- 4.78 (s, 1H), 3.61 (s,2H), 2.81- 349.4 (M + H) yl)methyl)phenyl)ethylcarbamate 2.69 (m, 8H),2.44 (s, 3H), 1.94- 1.85 (m, 2H), 1.43 (br s, 12H) 78:(S)-1-(4-((4-methyl-1,4-diazepan- MS m/z 1-yl)methyl)phenyl)ethanamine248.1 (M + H) 79: (S)-1-(4-((4-tert-butylpiperazin-1- MS m/zyl)methyl)phenyl)ethanamine 276.2 (M + H) 80: (S)-1-(4-((3,3,4- MS m/ztrimethylpiperazin-1- 262.2 (M + H) yl)methyl)phenyl)ethanamine 81:(S)-tert-butyl 1-(4-((4- (CDCl₃) 7.28-7.22 (m, 4H), 4.78 MS m/zisopropylpiperazin-1- (s, 1H), 3.49 (s, 2H), 2.88- 363.4 (M + H)yl)methyl)phenyl)ethylcarbamate 2.22 (m, 9H), 1.42 (br s, 12H), 1.05 (d,J = 6.5 Hz, 6H) 82: (S)-1-(4-((4-isopropylpiperazin-1- MS m/zyl)methyl)phenyl)ethanamine 262.2 (M + H) 83: (1S)-1-(4-((3,4- MS m/zdimethylpiperazin-1- 248.2 (M + H) yl)methyl)phenyl)ethanamine 84:(S)-tert-butyl 1-(4-((4,4- MS m/z difluoropiperidin-1- 356.2 (M + H)yl)methyl)phenyl)ethylcarbamate 85: (S)-1-(4-((4,4-difluoropiperidin-1-MS m/z yl)methyl)phenyl)ethanamine 255.2 (M + H) 86: (S)-tert-butyl1-(3-fluoro-4-(4- (CDCl₃) 8.01 (t, J = 8.1 Hz, 1H), MS m/z(2,2,2-trifluoroethoxy) 7.16 (d, J = 7.9, 1H), 7.04 (d, J = 463.3 (M +H) cyclohexylcarbamoyl) 13.2, 1H), 6.67-6.63(m, 1H),phenyl)ethylcarbamate 4.96 (br s, 1H), 4.76 (br s, 1H), 4.06 (br s, 1H),3.85-3.77 (m, 2H), 3.64 (br s, 1H), 1.92-1.74 (m, 4H), 1.73-1.59 (m,4H), 1.40 (br s, 12H) 87: (S)-4-(1-aminoethyl)-2-fluoro-N- MS m/z(4-(2,2,2- 363.2 (M + H) trifluoroethoxy)cyclohexyl)benzamide 88:(S)-tert-butyl 1-(3-fluoro-4-(4- (CDCl₃) 8.04 (t, J = 8.1 Hz, 1H), MSm/z hydroxy-4- 7.19 (d, J = 8.3, 1H), 7.05 (dd, J = 395.1 (M + H)methylcyclohexylcarbamoyl) 13.2, 1.7 Hz, 1H), 6.65 (br dd,phenyl)ethylcarbamate J = 12.1, 6.6 Hz, 2H), 4.84 (br s, 1H), 4.77 (brs, 1H), 4.17- 4.06 (m, 1H), 2.09-2.00 (m, 2H), 1.61-1.59 (m, 4H), 1.55-1.47 (m, 2H), 1.42 (br s, 12H), 1.30 (s, 3H) 89:(S)-4-(1-aminoethyl)-2-fluoro-N- MS m/z (4-hydroxy-4- 295.2 (M + H)methylcyclohexyl)benzamide 90: tert-butyl (1S)-1-(3-fluoro-4- MS m/z((hexahydropyrrolo[1,2-a]pyrazin- 376.1 (M − H) 2(1H)-yl)methyl)phenyl)ethylcarbamate 91: (1S)-1-(3-fluoro-4- MS m/z((hexahydropyrrolo[1,2-a]pyrazin- 278.1 (M + H)2(1H)-yl)methyl)phenyl)ethanamine 92: (S)-1-(4-((4-cyclopropylpiperazin-MS m/z 1-yl)methyl)phenyl)ethanamine 260.2 (M + H) 93: tert-butyl(1S)-1-(4-((dihydro-1H- (CDCl₃) 7.30-7.20 (m, 4H), MS m/zpyrido[1,2-a]pyrazin- 4.78 (s, 2H), 3.46 (s, 2H), 2.89- 372.4 (M − H)2(6H,7H,8H,9H,9aH)- 2.61 (m, 4H), 2.39-2.21 (m,yl)methyl)phenyl)ethylcarbamate 2H), 2.10-1.93 (m, 2H), 1.86 (t, J =10.7 Hz, 1H), 1.79-1.68 (m, 1H), 1.62 (br s, 2H), 1.43 (br s, 13H),1.32-1.19 (m, 2H) 94: (1S)-1-(4-((dihydro-1H- MS m/zpyrido[1,2-a]pyrazin- 274.2 (M + H) 2(6H,7H,8H,9H,9aH)-yl)methyl)phenyl)ethanamine 95: tert-butyl (1S)-1-(4-((3-methyl- MS m/z3,8-diazabicyclo[3.2.1]octan-8- 361.3 (M + H)yl)methyl)phenyl)ethylcarbamate 96: (1S)-1-(4-((3-methyl-3,8- MS m/zdiazabicyclo[3.2.1]octan-8- 260.2 (M + H) yl)methyl)phenyl)ethanamine97: tert-butyl (1S)-1-(4-((8-methyl- (CDCl₃) 7.28-7.19 (m, 4H), MS m/z3,8-diazabicyclo[3.2.1]octan-3- 4.77 (br s, 2H), 3.44 (s, 2H), 360.6(M + H) yl)methyl)phenyl)ethylcarbamate 3.03 (br s, 2H), 2.55 (dd, J =10.8, 2.9 Hz, 2H), 2.29 (d, J = 10.3 Hz, 2H), 2.25 (s, 3H), 1.93- 1.78(m, 4H), 1.64 (br s, 1H), 1.43 (br s, 12H) 98: (1S)-1-(4-((8-methyl-3,8-MS m/z diazabicyclo[3.2.1]octan-3- 260.2 (M + H).yl)methyl)phenyl)ethanamine 99: tert-butyl (1S)-1-(4- (CDCl₃) 7.30-7.21(m, 4H), MS m/z ((hexahydropyrrolo[1,2-a]pyrazin- 4.78 (br s, 1H),3.61-3.44 (m, 361.3 (M + H) 2(1H)- 2H), 3.05 (td, J = 8.6, 1.9 Hz,yl)methyl)phenyl)ethylcarbamate 1H), 3.00-2.93 (m, 2H), 2.86- 2.76 (m,1H), 2.33-2.19 (m, 2H), 2.17-2.00 (m, 2H), 1.87- 1.65 (m, 4H), 1.43 (brs, 12H) 100: (1S)-1-(4- MS m/z ((hexahydropyrrolo[1,2-a]pyrazin- 260.2(M + H) 2(1H)-yl)methyl)phenyl)ethanamine 101:(S)-1-[4-(4-Fluoro-phenoxy)- LC-MS m/z cyclohexyl]-ethylamine 237.4 (M +H)+; RT.: 1.08 min. 102: (S)-tert-butyl 1-(4-((4- (CDCl₃) 7.28-7.20 (m,4H), MS m/z (dimethylamino)piperidin-1- 4.79 (br s, 2H), 3.46 (s, 2H),361.8 (M + H) yl)methyl)phenyl)ethylcarbamate 2.91 (br d, J = 12.1 Hz,2H), 2.26 (s, 6H), 2.17-2.09 (m, 1H), 1.94 (td, J = 11.8, 2.4 Hz, 2H),1.85 (br s, 1H), 1.81-1.71 (m, 2H), 1.53 (td, J = 12.1, 3.7 Hz, 2H),1.44-1.42 (m, 12H) 103: (S)-1-(4-(1-aminoethyl)benzyl)- MS m/zN,N-dimethylpiperidin-4-amine 262.1 (M + H) 104: tert-butyl(1S)-1-(4-((3,5- (CD₃OD) 7.29 (s, 4 H), 4.68 (br MS m/zdimethylpiperazin-1- s, 1 H), 3.52 (s, 2 H), 2.96- 348.3 (M + H)yl)methyl)phenyl)ethylcarbamate 2.88 (m, 2H), 2.82-2.79 (m, 2 H), 1.69(t, J = 11 Hz, 2 H), 1.44 (br s, 9 H), 1.40 (d, J = 7.1 Hz, 3 H), 1.06(d, J = 6.5 Hz, 6 H); 105: (S)-tert-butyl 1-(4-((3,3,4- (CD₃OD) δ7.35-7.25 (m, 4 H), MS m/z trimethylpiperazin-1- 4.67 (br s, 1 H), 4.59(s, 1 H), 362.3 (M + H) yl)methyl)phenyl)ethylcarbamate 3.45 (s, 2 H),3.31 (s, 1 H), 2.62 (br s, 2 H), 2.51 (br s, 1 H), 2.24 (s, 3 H), 2.18(br s, 1 H), 1.43 (br s, 9 H), 1.40 (d, J = 7.1 Hz, 3 H), 1.07 (s, 6 H);106: ((S)-tert-butyl 1-(4-((4- (CDCl₃) δ 7.21-7.16 (m, 4 H), MS m/zcyclopropylpiperazin-1- 5.23 (s, 1 H), 4.72 (br s, 1 H), 359.8 (M + H)yl)methyl)phenyl)ethylcarbamate 3.42 (s, 2 H), 2.58 (br s, 4 H), 2.38(br s, 4 H), 1.57-1.51 (m, 1 H), 1.41-1.30 (br m, 12 H), 0.39-0.33 (m, 4H); 107: (S)-tert-butyl 1-(4-((tert- (CDCl₃) 7.32 (d, J = 8.0 Hz, MS m/z308.2 butylamino)methyl)phenyl) 1H), 7.25 (d, J = 8.2 Hz, 1H), (M + H)+ethylcarbamate 4.77 (s, 1H), 3.72 (s, 1H), 1.43 (d, J = 5.4 Hz, 6H),1.18 (s, 4H) 108: (S)-N-(4-(1-aminoethyl)benzyl)- MS m/z 207.22-methylpropan-2-amine (M + H)+ 109: (S)-tert-butyl 1-(4-(tert- (CDCl₃)7.71-7.62 (m, 2H), MS m/z 321.2 butylcarbamoyl)phenyl)ethyl 7.33 (d, J =8.1 Hz, 2H), 5.90 (M + H)+ carbamate (s, 1H), 4.80 (br s, 2H), 1.46-1.41 (m, 21H) 110: (S)-4-(1-aminoethyl)-N-tert- MS m/z 221.3butylbenzamide hydrochloride (M + H)+ 111: (S)-tert-butyl 1-(4- (CDCl₃)7.71 (dd, J = 8.3, 1.8 MS m/z 347.2 (cyclohexylcarbamoyl)phenyl)ethylHz, 2H), 7.35 (d, J = 7.8 Hz, (M + H)+ carbamate 2H), 5.91 (d, J = 8.3Hz, 1H), 4.94-4.59 (m, 2H), 3.97 (ddt, J = 10.8, 6.5, 2.9 Hz, 1H), 2.02(dt, J = 12.6, 3.7 Hz, 2H), 1.75 (dp, J = 11.8, 3.9 Hz, 2H), 1.66- 1.56(m, 3H), 1.49-1.30 (m, 12H), 1.23 (m, 3H) 112: (S)-4-(1-aminoethyl)-N-MS m/z 247.3 cyclohexylbenzamide hydrochloride (M + H)+ 113:(S)-tert-butyl 1-(4- (CDCl₃) 7.90-7.83 (m, 2H), MS m/z 340.6(phenylcarbamoyl)phenyl)ethyl 7.81-7.62 (m, 3H), 7.49- (M + H)+carbamate 7.36 (m, 4H), 7.18 (td, J = 7.4, 1.2 Hz, 1H), 4.87 (br s, 2H),1.58 (s, 3H), 1.46 (m, 9H) 114: (S)-4-(1-aminoethyl)-N- MS m/z 241.2phenylbenzamide hydrochloride (M + H)+ 115: (S)-tert-butyl1-(4-(piperidine-1- (CDCl₃) 7.33 (q, J = 8.3 Hz, MS m/z 333.2carbonyl)phenyl)ethylcarbamate 4H), 4.80 (br s, 2H), 3.70 (br s, (M +H)+ 2H), 3.47-3.22 (m, 2H), 1.70- 1.63 (m, 4H), 1.53-1.26 (m, 14H) 116:(S)-(4-(1-aminoethyl)phenyl) MS m/z 233.2 (piperidin-1-yl)methanone (M +H)+ hydrochloride 117: (S)-tert-butyl 1-(4-(4- (CDCl₃) 7.35 (q, J = 8.2Hz, MS m/z 348.2 methylpiperazine-1- 4H), 4.81 (br s, 1H), 3.79 (brs,(M + H)+ carbonyl)phenyl)ethylcarbamate 2H), 3.45 (br s, 2H), 2.50-2.32(m, 7H), 1.61 (s, 1H), 1.51- 1.29 (m, 12H) 118:(S)-(4-(1-aminoethyl)phenyl)(4- MS m/z 248.2methylpiperazin-1-yl)methanone (M + H)+ hydrochloride 119:(S)-tert-butyl 1-(4-(piperidin-1- (CDCl₃) 7.27 (q, J = 7.9 Hz, MS m/z319.0 ylmethyl)phenyl)ethylcarbamate 4H), 4.80 (br s, 2H), 3.49 (s, (M +H)+ 2H), 2.60-2.28 (m, 4H), 1.60 (p, J = 5.5 Hz, 4H), 1.52-1.31 (m, 15H)120: (S)-1-(4-(piperidin-1- MS m/z 219.1 ylmethyl)phenyl)ethanamine (M +H)+ 121: (S)-tert-butyl 1-(4- (CDCl₃) 7.48-7.10 (m, 4H), MS m/z 321.2(morpholinomethyl)phenyl)ethyl 4.82 (d, J = 25.7 Hz, 2H), 3.80- (M + H)+carbamate 3.62 (m, 3H), 3.48 (s, 2H), 2.61-2.24 (m, 3H), 1.44 (m, 13H)122: (S)-1-(4-(morpholinomethyl) MS m/z 220.9 phenyl)ethanamine M + H)+123: (S)-tert-butyl 1-(4-((4- (CDCl₃) 7.39-7.15 (m, 7H), MS m/z 321.2methylpiperazin-1- 4.79 (br s, 2H), 3.51 (s, 2H), (M + H)+yl)methyl)phenyl)ethylcarbamate 2.41 (m, 9H), 1.46 (m, 11H) 124:(S)-1-(4-((4-methylpiperazin-1- MS m/z 234.2 yl)methyl)phenyl)ethanamine(M + H)+ 125: 4-((S)-1-Amino-ethyl)- LC-MS (M + H) =piperidine-1-carboxylic acid benzyl 263.1 RT.: ester 0.91 min.

Intermediate 126 (S)-(4-(1-aminoethyl)-3-fluorophenyl)methanol

To a cooled (0° C.) suspension of (S)-methyl4-(1-aminoethyl)-3-fluorobenzoate hydrochloride (0.109 g, 0.468 mmol) inTHF (15 mL) was added a solution of LAH in THF (2.0 M, 1.05 mL, 2.10mmol, 4.49 equiv) and the resulting mixture was stirred at 0° C. for 2 h20 min and at room temperature for 2½ h. The reaction mixture wasquenched by addition of a mixture of Na₂SO₄ decahydrate and Celite (1:1by weight) until gas evolution ceased. The reaction mixture wasfiltered, washed with EtOAc. The filtrate was concentrated and used forthe next reaction without purification.

¹H NMR (400 MHz, CD₃OD) δ 7.43 (t, J=7.7 Hz, 1H), 7.15 (d, J=8.1 Hz,1H), 7.08 (d, J=12 Hz, 1H), 4.60 (s, 2H), 4.32 (q, J=6.6 Hz, 1H),1.42-1.40 (m, 3H).

Intermediate 1274-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzaldehyde

A solution of(S)-3-(2-((S)-1-(4-(hydroxymethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one(285 mg, 0.8 mmol) and manganese dioxide (2.78 g, 32 mmol, 40 equiv) inDCM (16 mL) was stirred at room temperature for 30 min. The solution wasfiltered through a pad of celite and washed with DCM. The filtrated wasconcentrated and used to next step without further purification.

Intermediate 128 tert-butyl4-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzyl)-2,2-dimethylpiperazine-1-carboxylate

A solution of4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzaldehyde(71 mg, 0.2 mmol) and tert-butyl 2,2-dimethylpiperazine-1-carboxylate(47.1 mg, 0.22 mmol) in MeOH (4 mL) was added acetic acid (14.4 mg, 0.24mmol) and 5-Ethyl-2-methylpyridine borane complex (27 mg, 0.2 mmol,sigma aldrich). The solution was stirred at 50° C. for 4 h then 5 dropsof water was added. The solution was stirred at room temperature foranother 2 h then diluted with EtOAc (10 mL) and washed with water (10mL). After separation, the aqueous phase was extracted with EtOAc (3×10mL). Combined organics were dried over Na₂SO₄, filtered andconcentrated. The crude material was purified through Silica gel columnchromatography (MeOH/EtOAc 0 to 10%) to give tert-butyl4-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzyl)-2,2-dimethylpiperazine-1-carboxylateas a white solid (80 mg, 72.4% yield).

¹H NMR (400 MHz, CDCl₃) δ 8.18 (br s, 1H), 7.44 (d, J=5.7 Hz, 1H),7.24-7.29 (m, 4H), 5.46 (br s, 1H), 5.03 (br s, 1H), 4.59-4.63 (m, 1H),4.29 (t, J=8.7 Hz, 1H), 4.22 (dd, J=9.1, 3.1 Hz, 1H), 3.44 (br s, 4H),2.40 (s, 2H), 2.16 (s, 2H), 1.54 (d, J=6.9 Hz, 3H), 1.45 (s, 9H), 1.36(s, 6H), 0.80-0.57 (m, 6H); MS m/z 252.1 (M+H).

Intermediate 129 tert-butyl1-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzyl)-4-methylpiperidin-4-ylcarbamate

Prepared by a method similar to that described for the preparation ofIntermediate 128.

¹H NMR (400 MHz, CDCl₃) 8.17 (d, J=5.7 Hz, 1H), 7.43 (d, J=5.7 Hz, 1H),7.26 (br s, 4H), 5.40 (br s, 1H), 5.02 (br s, 1H), 4.60 (dt, J=8.2, 3.1Hz, 1H), 4.34-4.19 (m, 3H), 3.47 (br s, 2H), 2.54 (br s, 2H), 2.26 (brs, 2H), 1.95 (br s, 3H), 1.60 (br s, 2H), 1.53 (d, J=6.9 Hz, 3H), 1.43(s, 9H), 1.33 (s, 3H), 0.69 (br s, 3H), 0.63 (br s, 3H). MS m/z 553.6(M+H).

Intermediate 130 tert-butyl(S)-1-(4-bromophenyl)ethyl(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)carbamate

To a solution of(S)-3-(2-((S)-1-(4-bromophenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one(1.62 g, 4 mmol) in THF (20 mL) was added di-tert-butyl dicarbonate(1.31 g, 6 mmol), DMAP (49 mg, 0.4 mmol) and DIPEA (1.40 mL, 8 mmol).The solution was stirred at 50° C. for 7 days then concentrated underreduced pressure. The residue was diluted with EtOAc (40 mL) and washedwith water and brine. The organic layer was dried over Na₂SO₄, filteredand concentrated. Silica gel column chromatography (EtOAc/heptane 0 to80%) provided tert-butyl(S)-1-(4-bromophenyl)ethyl(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)carbamateas a white solid (1.03 g, 50.9% yield).

¹H NMR (400 MHz, CDCl₃) δ 8.57 (d, J=5.8 Hz, 1H), 7.99 (d, J=5.8 Hz,1H), 7.44-7.39 (m, 2H), 7.33-7.28 (m, 2H), 5.63 (q, J=7.2 Hz, 1H), 4.63(dt, J=8.0, 3.3 Hz, 1H), 4.39-4.26 (m, 2H), 2.47-2.39 (m, 1H), 1.66 (d,J=7.1 Hz, 3H), 1.30 (s, 9H), 0.84 (d, J=7.0, 3H), 0.83 (d, J=7.0, 3H);MS m/z 507.0 (M+H).

Intermediate 131 tert-butyl4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl((S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)carbamate

In a 5 mL microwave vial a solution of tert-butyl(S)-1-(4-bromophenyl)ethyl(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)carbamate(101 mg, 0.2 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50mg, 0.24 mmol), Sodium bicarbonate (0.2 mL, 0.4 mmol, 2 M aqueoussolution) in Dioxane (2 mL) was bubbled N2 for 3 min thenCl₂Pd(dppf)CH₂Cl₂ (16 mg, 0.02 mmol) was added. The capped tube washeated to 100° C. for 16 h. After cooling the reaction mixture wasdiluted with EtOAc (10 mL) and washed with water (10 mL). Afterseparation, the aqueous phase was extracted with EtOAc (3×10 mL).Combined organics were dried over Na₂SO₄, filtered and concentrated. Thecrude material was purified through silica gel column chromatography(EtOAc in Heptane 12 to 100%) to give a white solid (50 mg, 49.3%yield).

¹H NMR (400 MHz, CDCl₃) δ 8.57 (d, J=5.7 Hz, 1H), 7.97 (d, J=5.8 Hz,1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.39 (s, 4H), 5.71 (q, J=7.0 Hz, 1H),4.65 (dt, J=8.1, 3.2 Hz, 1H), 4.36-4.24 (m, 2H), 3.94 (s, 3H), 2.50-2.42(m, 1H), 1.71 (d, J=7.0 Hz, 3H), 1.29 (s, 9H), 0.82 (d, J=7.0 Hz, 3H),0.80 (d, J=7.0 Hz, 3H); MS m/z 507.1 (M+H).

Intermediate 132 tert-butyl(S)-1-(4-(cyclohexanecarboxamido)phenyl)ethyl(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)carbamate

In a 5 ml microwave reaction vial was added tert-butyl(S)-1-(4-bromophenyl)ethyl(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)carbamate(101 mg, 0.2 mmol), cyclohexanecarboxamide (30 mg, 0.24 mol), cesiumcarbonate (91 mg, 0.28 mmol), XANTPHOS (7 mg, 0.012 mmol, stremchemicals), and Pd₂(dba)₃ (4 mg, 0.02 mmol). The vial was sealed,evacuated and purged with dry nitrogen three times before adding dioxane(1.6 mL). The reaction mixture was heated to 100° C. for 16 hours in anoil bath. After cooling the reaction was diluted with EtOAc (10 mL) andwashed with water (10 mL). After separation, the aqueous phase wasextracted with EtOAc (3×10 mL). Combined organics were dried overNa₂SO₄, filtered and concentrated. The crude material was purifiedthrough silica gel column chromatography (EtOAc in Heptane 12 to 100%)to give a white solid (65 mg, 58.9% yield).

¹H NMR (400 MHz, CDCl₃) δ 8.55 (d, J=5.8 Hz, 1H), 7.95 (d, J=5.8 Hz,1H), 7.48-7.43 (m, 2H), 7.38-7.32 (m, 2H), 7.13 (br s, 1H), 5.66 (q,J=7.1 Hz, 1H), 4.64 (dt, J=8.2, 3.2 Hz, 1H), 4.38-4.26 (m, 2H),2.51-2.43 (m, 1H), 2.20 (tt, J=11.8, 3.5 Hz, 1H), 1.95 (d, J=13.2, 2H),1.87-1.81 (m, 2H), 1.71-1.68 (m, 4H), 1.60-1.47 (m, 2H), 1.33-1.25 (m,12H), 0.85 (d, J=6.9 Hz, 3H), 0.82 (d, J=6.9 Hz, 3H); MS m/z 552.1(M+H).

Intermediate 133 (S)-methyl2-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)propanoate

To a solution of (S)-methyl 2-aminopropanoate (270 mg, 2.0 mmol, 1.2equv. in 10 ml of DMSO) and(S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (430 mg, 1.8mmol, 1.0 equv.) was added DIPEA (805 mg, 6.23 mmol, 3.5 equiv), and thereaction mixture was heated at 110° C. for 120 min. The reaction mixturewas poured into water (40 ml) and extracted with EtOAc (2×30 mL) andwashed with water (30 mL). After separation, the aqueous phase wasextracted with EtOAc (3×8 mL). Combined organics were dried over Na₂SO₄,filtered and concentrated. Silica gel column chromatography (ethylacetate in heptane 10 to 80%) to provide (S)-methyl2-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)propanoate(260 mg, white solid) in 47.4% yield. LCMS m/z 309.1 (M+H)⁺ RT=1.53 min.

Intermediate 134(S)-2-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)propanehydrazide

To a solution of (S)-methyl2-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)propanoate(120 mg, 0.39 mmol in 5 ml of MeOH) was added 99% hydrazine hydrate, thereaction solution was stirred at room temperature overnight (24 hours),the solvent was removed to yield the desired product (99 mg) in 78%yield, and was used for next step without purification. LCMS m/z 309.1(M+H)⁺ RT=1.25 min.

Intermediate 135 (S)-tert-butyl (1-hydrazinyl-1-oxopropan-2-yl)carbamate

A solution of hydrazine (234 mg, 7.31 mmol, 1.5 equv. in 8 ml of THF)was added to (S)-methyl 2-(tert-butoxycarbonylamino)propanoate (1000 mg,4.88 mmol, 1.0 equv.), it was stirred in a sealed tube and refluxed (72°C.) overnight (18 hours), the solvent was removed to yield the desiredproduct (880 mg, white solid) in 84% yield.

Intermediate 136 (S)-tert-butyl(1-(2-benzoylhydrazinyl)-1-oxopropan-2-yl)carbamate

To a solution of (S)-tert-butyl (1-hydrazinyl-1-oxopropan-2-yl)carbamate(293 mg, 1.44 mmol, 1.0 equv. in 3 ml of DCM) was added benzoyl fluoride(179 mg, 1.44 mmol in 2 ml of DCM), the reaction solution was stirred atroom temperature for 50 min., the solvent was removed to yield thedesired product. ¹H NMR (400 MHz, CDCl₃) δ 7.89-7.78 (m, 2H), 7.54 (t,J=7.4 Hz, 1H), 7.43 (t, J=7.6 Hz, 2H), 5.32 (b, 1H), 4.45 (b, 1H), 1.46(s, 9H).

Intermediate 137 (S)-tert-butyl(1-(5-phenyl-1,3,4-thiadiazol-2-yl)ethyl)carbamate

To a solution of (S)-tert-butyl(1-(2-benzoylhydrazinyl)-1-oxopropan-2-yl)carbamate (155 mg, 0.5 mmol,1.0 equv. in 5 ml of THF) was added Lawesson's reagent (36.4 mg, 0.5mmol, 1.0 equv.) the reaction mixture was stirred at reflux for 3 hours,the reaction mixture was filtered and the solvent was removed to yieldthe crude product. Silica gel column chromatography (ethyl acetate inheptane 10 to 50%) to provide (S)-tert-butyl(1-(5-phenyl-1,3,4-thiadiazol-2-yl)ethyl)carbamate (114.6 mg, whitesolid) in 70.7% yield. ¹H NMR (400 MHz, CD₂Cl₂) δ 7.94-7.72 (m, 2H),7.52-7.26 (m, 3H), 5.59 (b, 1H), 5.11 (b, 1H), 1.57 (d, J=7.0 Hz, 3H),1.34 (s, 9H).

Intermediate 138 (S)-1-(5-phenyl-1,3,4-thiadiazol-2-yl)ethanamine

To a solution of (S)-tert-butyl(1-(5-phenyl-1,3,4-thiadiazol-2-yl)ethyl)carbamate (110 mg, 0.4 mmol, in5 ml of DCM) was added 1 ml of TFA, the reaction mixture was stirred atroom temperature for 3 hours, the solvent was removed to yield thedesired product (52 mg) in 66.8% yield. LCMS m/z 206.0 (M+H)⁺ RT=0.97min.

Intermediate 139 1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone

A cloudy solution of 1-(5-bromopyrimidin-2-yl)ethanone (300 mg, 1.49mmol), 3-(trifluoromethyl)phenylboronic acid (567 mg, 2.98 mmol), K₃PO₄(950 mg, 4.48 mmol), DavePhos ligand[2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl] (59 mg, 0.15mmol), and Pd(OAc)₂ (17 mg, 0.075 mmol) in 6 mL toluene was heated at100° C. for 1 h. The mixture was cooled to room temperature, andfiltered through Celite. Filter cake was rinsed with 30 mL EtOAc. Thefiltrate was poured into 20 mL water. Layers were separated, and theaqueous was further extracted with EtOAc (20 mL). Combined organics werewashed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, filteredand concentrated directly onto silica gel. Column chromatography(10-100% EtOAc/heptane) gave 0.26 g1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone (V) as tansolid. MS m/z 267.1 (M+H)+. ¹H NMR (400 MHz, CDCl₃) δ 9.16 (s, 2H),7.93-7.69 (m, 4H), 2.87 (s, 3H).

The Following intermediates were prepared using a method similar to thatdescribed for the preparation of Intermediate 139. Using Anal. RP-HPLCColumn=Inertsil C8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C.Eluents=A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2mL/min. Gradient=0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1min 1% B.)

Intermediate 140 1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethanone

Anal. RP-HPLC tR=1.17 min. MS m/z 266.9 (M+H)+.

Intermediate 141 1-(5-(3-fluoro-2-methylphenyl)pyrimidin-2-yl)ethanone

Anal. RP-HPLC tR=1.07 min. MS m/z 231.1 (M+H)+.

Intermediate 142 1-(5-(4-fluoro-2-methylphenyl)pyrimidin-2-yl)ethanone

Anal. RP-HPLC tR=1.18 min. MS m/z 231.1 (M+H)+.

Intermediate 143 1-(5-(5-fluoro-2-methylphenyl)pyrimidin-2-yl)ethanone

Anal. RP-HPLC tR=1.16 min. MS m/z 231.2 (M+H)+.

Intermediate 144 1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethanone

¹H NMR (400 MHz, CDCl₃) δ 9.09 (s, 2H), 7.52-7.41 (m, 2H), 7.24-7.16 (m,1H), 2.85 (s, 3H), 2.41 (d, J=2.0 Hz, 3H). Anal. RP-HPLC tR=1.20 min. MSm/z 231.0 (M+H)+.

Intermediate 145 1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethanone

Anal. RP-HPLC tR=1.15 min. MS m/z 267.9 (M+H)+.

Intermediate 146 1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethanone

¹H NMR (400 MHz, CDCl₃) δ 8.88 (dd, J=2.3, 0.8 Hz, 1H), 8.13 (dd, J=8.1,0.8 Hz, 1H), 7.98 (dd, J=8.1, 2.3 Hz, 1H), 7.50-7.39 (m, 2H), 7.21-7.12(m, 1H), 2.78 (s, 3H), 2.42-2.36 (m, 3H). Anal. RP-HPLC tR=1.40 min. MSm/z 230.8 (M+H)+.

Intermediate 1471-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanamine

1-(5-(3-(Trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone (260 mg, 0.977mmol), NH4—OAc (1.13 g, 14.6 mmol), and NaBH3CN (245 mg, 3.91 mmol) weretaken up in 8 mL 200 proof EtOH, and heated at 120° C. for 5 minutes ina microwave apparatus. The mixture was concentrated to remove the EtOH.Crude was taken up in 30 ml water+25 mL EtOAc. 6N NaOH was added untilaqueous pH was ˜10. Separated layers, and extracted aqueous with EtOAc(25 ml). The combined organic layer was washed with 25 mL brine anddried with Na₂SO₄. Filtered and concentrated with reduced pressure togive 262 mg crude yellow oil, which was carried forward without furtherpurification. Anal. RP-HPLC tR=0.90 min. (Column=Inertsil C8 Column, 3.0μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammoniumformate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 268.1 (M+H)+.

The Following intermediates were prepared using a method similar to thatdescribed for the preparation of Intermediate 147.

Intermediate 148 1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethanamine

Anal. RP-HPLC tR=1.09 min (Gradient: 2 to 98% B in 1.7 min—flow 1mL/min. Eluent A: Water+3.75 mM NH4Ac+2% ACN. Column: Acquity CSH 1.7 μm2.1×50 mm—50° C.) MS m/z 268.4 (M+H)+.

Intermediate 149 1-(5-(3-fluoro-2-methylphenyl)pyrimidin-2-yl)ethanamine

Anal. RP-HPLC tR=0.99 min. (Gradient: 2 to 98% B in 1.7 min—flow 1mL/min. Eluent A: Water+3.75 mM NH4Ac+2% ACN. Column: Acquity CSH 1.7 μm2.1×50 mm—50° C.) MS m/z 232.4 (M+H)+.

Intermediate 150 1-(5-(4-fluoro-2-methylphenyl)pyrimidin-2-yl)ethanamine

Anal. RP-HPLC tR=0.87 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate,2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 231.0 (M)−.

Intermediate 151 1-(5-(5-fluoro-2-methylphenyl)pyrimidin-2-yl)ethanamine

Anal. RP-HPLC tR=0.79 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate,2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 232.0 (M+H)+.

Intermediate 152 1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethanamine

Anal. RP-HPLC tR=0.81 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate,2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 231.9 (M+H)+.

Intermediate 153 1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethanamine

Anal. RP-HPLC tR=1.01 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate,2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 269.0 (M+H)+.

Intermediate 154 1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethanamine

Anal. RP-HPLC tR=0.92 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate,2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 230.9 (M+H)+.

Intermediate 155 1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanamine

Step 1: A solution of 1-(5-fluoropyrimidin-2-yl)ethanone (700 mg, 5.0mmol) and 4-fluorophenol (616 mg, 5.50 mmol) in 6 mL DMF was treatedwith potassium carbonate (829 mg 6.0 mmol) and heated to 50° C. for 3.5h. The reaction mixture was poured into 20 mL water, and extracted withEtOAc (2×20 mL). Organics were washed with 20 mL each water, brine, anddried over Na₂SO₄. Mixture was filtered and concentrated on silica gel.Column chromatography (10-100% EtOAc/hept) gave 295 mg (25%)1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanone as a white solid useddirectly in the following step. MS m/z 233.2 (M+H)+. ¹H NMR (400 MHz,CDCl₃) δ 8.55 (s, 2H), 7.23-7.07 (m, 4H), 2.78 (s, 3H).

Step 2: 1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanone (290 mg, 1.25mmol), NH4OAc (1.9 g, 24.6 mmol), and NaBH₃CN (314 mg, 5.00 mmol) weretaken up in 20 mL 200 proof EtOH, and heated at 130 C for 3 minutes in amicrowave apparatus. The mixture was concentrated to remove the EtOH.Crude was taken up in 30 ml water+25 mL EtOAc. 6N NaOH was added untilaqueous pH was ˜10. Separated layers, and extracted aqueous with EtOAc(25 ml). The combined organic layer was washed with 25 mL brine anddried with Na₂SO₄. Filtered and concentrated with reduced pressure togive 275 mg crude tan oil, which was carried forward without furtherpurification. Major product Anal. RP-HPLC tR=1.26 min. (Column=InertsilC8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water(5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z234.1 (M+H)+.

The Following intermediates were prepared using methods similar to thosedescribed for the preparation of Intermediate 155.

Intermediate 156 1-(5-(2,4-difluorophenoxy)pyrimidin-2-yl)ethanamine

Anal. RP-HPLC tR=0.81 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate,2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 252.1 (M+H)+.

Intermediate 157 1-(5-(5-bromopyridin-3-yloxy)pyrimidin-2-yl)ethanamine

Anal. RP-HPLC tR=1.29 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate,2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 297.3 (M+H)+.

Intermediate 1581-(5-(3-chloro-4-fluorophenoxy)pyrimidin-2-yl)ethanamine

Anal. RP-HPLC tR=1.40 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate,2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 268.0 (M+H)+.

Intermediate 159 1-(5-(pyridin-3-yloxy)pyrimidin-2-yl)ethanamine

Anal. RP-HPLC tR=1.21 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate,2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 218.4 (M+H)+.

Intermediate 1601-(5-(5-(trifluoromethyl)pyridin-2-yloxy)pyrimidin-2-yl)ethanamine

Anal. RP-HPLC tR=1.16 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate,2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 285.4 (M+H)+.

Intermediate 161 4-(4-fluorophenoxy)pyrimidine-2-carbonitrile

A solution of 4-chloropyrimidine-2-carbonitrile (0.63 g, 4.51 mmol) and4-fluorophenol (0.51 g, 4.51 mmol) in 5 mL DMF was cooled to 0° C. underN2 atmosphere. NaH (0.217 g of 60% suspension, 5.42 mmol) was slowlyadded. Bubbling exotherm observed.

Internal temp was kept below 5° C. After 15 minutes, cold bath wasremoved. The reaction mixture was allowed to warm to room temp and stir1 h. The reaction mixture was diluted with water (40 mL) and extractedwith (3×25 mL) EtOAc. The organic layer was washed with 40 mL eachwater, and brine. Dried over Na₂SO₄, and concentrated on silica gel invacuo. Column chromatography (EtOAc/heptane 10 to 100% gradient) gave0.72 g (74%) of (4-fluorophenoxy)pyrimidine-2-carbonitrile as acrystalline white solid. Anal. RP-HPLC tR=1.38 min, Gradient: 2 to 98% Bin 1.7 min—flow 1 mL/min. Eluent A: Water+3.75 mM NH4Ac+2% ACN. Column:Acquity CSH 1.7 μm 2.1×50 mm—50° C. MS m/z 216.1 (M+H)+.

Intermediate 162 1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanone

4-(4-fluorophenoxy)pyrimidine-2-carbonitrile (450 mg, 2.09 mmol) wassuspended in 12 mL anhydrous ether under N2 atmosphere. Vessel wascooled to 0° C. MeMgBr (3.1 mL of 1.0 M solution in butyl ether, 3.10mmol) was added over 5 min. The yellow-green suspension was stirred 30minutes, then quenched with 50 mL sat'd NH4Cl solution. Adjusted pH to˜6 with conc. HCl. The mixture was extracted with (2×40 mL) EtOAc.Washed organics with 30 mL brine, and dried over Na₂SO₄. Filtered andconcentrated on silica gel. Column chromatography (10-100% EtOAc inhept) gave 157 mg (32%) 1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanone asa yellow oil. Anal. RP-HPLC tR=1.44 min. (Column=Inertsil C8 Column, 3.0μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammoniumformate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 233.2 (M+H)+.

Intermediate 163 1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanol

1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanone (0.150 g 0.646 mmol) wastaken up in 2.5 mL 4:1 MeOH:DCM, and cooled to 0° C. NaBH₄ (49 mg 1.30mmol) was added. Fizzing was observed. After 10 min, cold bath wasremoved, and the reaction was stirred 1 h. Solvent was removed in vacuo.White residue was taken up in 10 mL water, and extracted with (2×10 mL)EtOAc. Washed organics with 10 mL brine. Dried over Na₂SO₄. Filtered andconcentrated to give 143 mg (95%)1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanol as a colorless oil. Anal.RP-HPLC tR=1.38 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30 mm.Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate, 2%ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 235.1 (M+H)+.

Intermediate 164 2-(1-azidoethyl)-4-(4-fluorophenoxy)pyrimidine

Under N₂ atmosphere, 1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanol (140mg, 0.598 mmol) was dissolved in 3 mL anhydrous DCM. Triethylamine(0.175 mL, 1.26 mmol) was added, and the mixture was cooled to 0° C.MsCl (0.070 mL, 0.897 mmol) was added, and the mixture was stirred 15minutes. Maintaining 0° C., DCM solvent was removed under N₂ stream.Residue was taken up in 2 mL dry DMF. NaN₃ (78 mg, 1.19 mmol) added, andthe reaction was stirred at rt for 24 h. Mixture was poured into 20 mLwater, and extracted with 20 mL EtOAc. Organic layer was washed with 20mL brine and dried over Na₂SO₄. Filtered and concentrated to give 120 mg(77%) 2-(1-azidoethyl)-4-(4-fluorophenoxy)pyrimidine as a yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 8.49 (d, J=5.7 Hz, 1H), 7.16-6.90 (m, 4H), 6.70(d, J=5.7 Hz, 1H), 4.34 (q, J=6.9 Hz, 1H), 1.55-1.46 (m, 3H).

Intermediate 165 1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanamine

2-(1-azidoethyl)-4-(4-fluorophenoxy)pyrimidine (120 mg, 0.463 mmol) wasdissolved in 2 mL neat EtOH. 24.6 mg (0.023 mmol) of 10% Palladium oncarbon catalyst was added. With vigorous stirring, the reaction vial wasevacuated and purged 3 times with H₂. The reaction vessel was fittedwith an H₂ balloon and stirred for 2 h. The mixture was filtered throughCelite and concentrated in vacuo to give 75 mg (69%)1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanamine as a brown oil. ¹H NMR(400 MHz, CDCl₃) δ 8.45 (d, J=5.7 Hz, 1H), 7.13-6.92 (m, 4H), 6.59 (d,J=5.7 Hz, 1H), 4.00 (q, J=6.8 Hz, 1H), 1.34-1.30 (m, 3H). Anal. RP-HPLCtR=1.18 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30 mm. ColumnTemperature=50° C. Eluents=A: Water (5 mM Ammonium formate, 2% ACN); B:ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in 1.70 min;0.3 min 95% B; 2.1 min 1% B.) MS m/z 234.2 (M+H)+.

The Following intermediates were prepared using methods similar to thosedescribed for the preparation of Intermediates 161 to 165.

Intermediate 166 1-(5-(4-fluorophenoxy)pyridin-2-yl)ethanamine

Anal. RP-HPLC tR=0.91 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate,2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 233.1 (M+H)+.

Intermediate 167 1-(5-(4-fluorophenoxy)pyrazin-2-yl)ethanamine

Anal. RP-HPLC tR=1.39 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate,2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 217.1 (Majorfragment+H)+.

Intermediate 168 1-(2-(4-fluorophenoxy)pyrimidin-5-yl)ethanamine

Anal. RP-HPLC tR=1.20 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate,2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 233.9 (M+H)+.

Intermediate 169(S)-4-Isopropyl-3-[2-((S)-1-methyl-prop-2-ynylamino)-pyrimidin-4-yl]-oxazolidin-2-one

To a solution of compound(S)-3-(2-Chloro-pyrimidin-4-yl)-4-isopropyl-oxazolidin-2-one (1.03 g,4.3 mmol) in DMSO (12 mL) was added methyl-prop-2-ynylamine HCl salt(450 mg, 4.3 mmol) and diisopropylethylamine (2.2 mL, 12.6 mmol). Thereaction was heated to 110 C for 18 hours. The reaction mixture wasdiluted with EtOAc (50 mL) and washed with water (25 mL) and brine (25mL). The organic layer was dried over Na₂SO₄, filtered and concentrated.The crude material was purified on silica gel column chromatography(EtOAc/Heptane 0 to 75%) provided(S)-4-Isopropyl-3-[2-((S)-1-methyl-prop-2-ynylamino)-pyrimidin-4-yl]-oxazolidin-2-one(360 mg) in 31% yield. LC-MS m/z: 275.1 (M−Boc)+; RT.: 1.33 min.

Intermediate 170 (S)-4,6-difluoro-N-(1-phenylethyl)pyrimidin-2-amine

A solution of 2,4,6-trifluoropyrimidine (128.4 mg, 0.96 mmol) andisopropylethylamine (0.50 mL, 2.9 mmol, 3 equiv) in dioxane (5 mL) wascooled to 0° C. with an ice bath. After 30 min, the ice bath wasremoved, and the reaction was allowed to warm to room temperature. Afterstirring overnight, the reaction was concentrated to a light brown oiland purified by silica gel column chromatography (EtOAc/Heptane 0 to100%) to provide (S)-4,6-difluoro-N-(1-phenylethyl)pyrimidin-2-amine(151.2 mg, white solid) in 45% yield. ¹H NMR (400 MHz, CD₃OD) δ7.35-7.40 (m, 2H), 7.29-7.34 (m, 2H), 7.20-7.26 (m, 1H), 5.84 (s, 1H),5.08 (q, J=6.91 Hz, 1H), 1.52 (d, J=7.04 Hz, 3H); LCMS m/z 236.1 (M+H)⁺,R_(t) 0.95 min.

Intermediate 171(S)-4,6-difluoro-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)pyrimidin-2-amine

Intermediate 171 was prepared by a method similar to the one describedfor the preparation of Intermediate 170. ¹H NMR (400 MHz, CD₃OD) 7.58(t, J=7.63 Hz, 1H), 7.34-7.48 (m, 2H), 5.84 (br. s., 1H), 5.35 (q,J=6.91 Hz, 1H), 1.54 (d, J=7.04 Hz, 3H). MS m/z 321.9 (M+H)+, Rt 1.11min.

Intermediate 172 tert-butyl 3-hydroxy-2-methylbutan-2-ylcarbamate

Step 1: Preparation of tert-butyl1-(methoxy(methyl)amino)-2-methyl-1-oxopropan-2-ylcarbamate

2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (6.62 g, 32.6 mmol),O,N-dimethylhydroxylamine hydrochloride (3.50 g, 35.8 mmol), and HATU(14.86 g, 39.1 mmol) were combined in DMF (100 mL). To this solution wasadded Hunig's Base (17.07 mL, 98 mmol). The reaction was stirred forovernight (17 hours). The reaction was then concentrated under vacuumand the residue was diluted with EtOAc (300 mL) and washed with water(2×80 mL). The organic layer was washed with brine, dried (Na₂SO₄), andconcentrated under reduced pressure. The residue was purified via silicagel flash chromatography (10-50 percent EtOAc-Hexanes) to afford thedesired product as a white solid (6.36 g). LCMS m/z 247.2 (M+H)⁺, Rt0.61 min.

Step 2: Preparation of tert-butyl 2-methyl-3-oxobutan-2-ylcarbamate

To a solution of tert-butyl1-(methoxy(methyl)amino)-2-methyl-1-oxopropan-2-ylcarbamate (4.26 g,17.30 mmol) in THF (100 mL) at −70° C. was added drop wise methyllithium (32.4 mL, 51.9 mmol). Cold bath was replaced with −40° C. bathand the reaction was stirred for 4 hours. Saturated NH₄Cl solution (10mL) was then added cautiously to quench the reaction. The reactionmixture was then allowed to warm to room temperature, and diluted withEtOAc (100 mL) and water (50 mL). The phases were separated and theaqueous layer was extracted with EtOAc (2×100 mL). The combined organicswere then dried (Na₂SO₄) and concentrated under reduced pressure. Theresidue was purified via silica gel flash chromatography (10-50%EtOAc-Hexanes) to afford the desired product as a white solid (2.36 g).LCMS m/z 224.2 (M+Na)⁺, Rt 0.7 min.

Step 3: Preparation of tert-butyl 3-hydroxy-2-methylbutan-2-ylcarbamate

To a solution of tert-butyl 2-methyl-3-oxobutan-2-ylcarbamate (2.36 g,11.73 mmol) in MeOH (30 mL) at 0° C. was added portion wise NaBH₄ (0.887g, 23.45 mmol). Cold bath was removed and the reaction was stirred for 1hour. HCl solution (1 M, 0.2 mL) was then added cautiously to quench thereaction. The reaction mixture was then concentrated and diluted withEtOAc (50 mL) and water (10 mL). The phases were separated and theaqueous layer was extracted with EtOAc (2×20 mL). The combined organicswere then dried (Na₂SO₄) and concentrated under reduced pressure. Theresidue was purified via silica gel flash chromatography (10-50%EtOAc-Hexanes) to afford the desired product as a white solid (2.12 g).LCMS m/z 204.1 (M+H)⁺, Rt 0.69 min.

Intermediate 173 tert-butyl((3S)-2-hydroxy-4-methylpentan-3-yl)carbamate

Step 1: Preparation of tert-butyl1-(methoxy(methyl)amino)-2-methyl-1-oxopropan-2-ylcarbamate

To a solution of (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid(5.86 g, 27.0 mmol) in DCM (100 mL) at 0° C. was added portion wisedi(1H-imidazol-1-yl)methanone (4.81 g, 29.7 mmol). Cold bath was removedand the reaction was stirred at 20° C. for 30 minutes.O,N-dimethylhydroxylamine hydrochloride (3.16 g, 32.4 mmol) was thenadded and followed by slow addition of triethylamine (3.28 g, 32.4mmol). The reaction mixture was stirred at 20° C. for overnight (18 hr),and diluted with DCM (200 mL) and washed with HCl (1 M, 2×50 mL) andsaturated NaHCO₃ solution (2×50 mL), H₂O (50 mL) and brine (50 mL). Theorganic was then dried (Na₂SO₄) and concentrated under reduced pressureto give crude product (6.61 g). LCMS m/z 261.2 (M+H)⁺, Rt 0.77 min.

Step 2: Preparation of (S)-tert-butyl 2-methyl-4-oxopentan-3-ylcarbamate

To a solution of (S)-tert-butyl1-(methoxy(methyl)amino)-3-methyl-1-oxobutan-2-ylcarbamate (4.23 g,16.25 mmol) in THF (100 mL) at −70° C. was added drop wise methyllithium (1.071 g, 48.7 mmol). Cold bath was replaced with −40° C. bath(MeCN in dry ice) removed and the reaction was stirred for 4 hours.Saturated NH₄Cl solution (10 mL) was then added cautiously to quench thereaction. The reaction mixture was then allowed to warm to roomtemperature, and diluted with EtOAc (100 mL) and water (50 mL). Thephases were separated and the aqueous layer was extracted with EtOAc(2×100 mL). The combined organics were then dried (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified via silicagel flash chromatography (10-50% EtOAc-Hexanes) to afford the desiredproduct as a white solid (3.01 g). LCMS m/z 238.2 (M+Na)⁺, Rt 0.78 min.

Step 3: Preparation of tert-butyl 3-hydroxy-2-methylbutan-2-ylcarbamate

To a solution of (S)-tert-butyl 2-methyl-4-oxopentan-3-ylcarbamate (2.65g, 12.31 mmol) in MeOH (30 mL) at 0° C. was added portion wise NaBH₄(0.931 g, 24.62 mmol). Cold bath was removed and the reaction wasstirred for 1 hour. HCl solution (1 M, 0.3 mL) was then added cautiouslyto quench the reaction. The reaction mixture was then concentrated anddiluted with EtOAc (50 mL) and water (10 mL). The phases were separatedand the aqueous layer was extracted with EtOAc (2×20 mL). The combinedorganics were then dried (Na₂SO₄) and concentrated. The residue waspurified via silica gel flash chromatography (10-50% EtOAc-Hexanes) toafford the desired product as a white solid (2.05 g). LCMS m/z 240.2(M+Na)⁺, Rt 0.69 min.

Intermediate 174 (S)-tert-butyl (1-cyclopropyl-2-hydroxyethyl)carbamate

Step 1: Preparation of tert-butyl1-(methoxy(methyl)amino)-2-methyl-1-oxopropan-2-ylcarbamate

To (S)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (5.01 g,23.28 mmol) in MeOH (50 mL) was added drop wisetrimethylsilyldiazomethane (18.62 ml, 37.2 mmol) until no bubbles. Thereaction was stirred for 30 minutes and quenched with drops of HOAc (0.1mL). The reaction mixture was then concentrated under reduced pressureto give crude product as a light tan oil (5.35 g). LCMS m/z 252.1(M+Na)⁺, Rt 0.77 min.

Step 2: Preparation of (S)-tert-butyl(1-cyclopropyl-2-hydroxyethyl)carbamate

To a solution of (S)-methyl2-(tert-butoxycarbonylamino)-2-cyclopropylacetate (5.35 g, 23.33 mmol)in Et₂O (100 ml) was added LiBH₄ (0.762 g, 35.0 mmol), followed by dropwise addition of methanol (1.420 ml, 35.0 mmol). The reaction wasrefluxed at 40° C. for one hour. The reaction mixture was then cooled to0° C., and quenched with HCl (1M) until pH=2 for aqueous layer. Thephases were separated and the aqueous layer was extracted with DCM(3×100 mL). The organic was then dried (Na₂SO₄) and concentrated underreduced pressure to give final crude product (4.16 g). LCMS m/z 224.1(M+Na)⁺, Rt 0.62 min.

Intermediate 175(R)—N—((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To an oven dried round bottom flask with stir bar was added4-bromo-2-fluorobenzaldehyde (5 g, 24.6 mmol),(R)-2-methylpropane-2-sulfinamide (3.28 g, 27.1 mmol) and DCE (49 mL).To this mixture was then added copper (II) sulfate (5.90 g, 36.9 mmol).Reaction mixture was heated in a preheated oil bath to 55° C. for 18hours. Reaction mixture was filtered through a pad celite, washing thesolids with CH₂Cl₂. The filtrate was concentrated to afford a viscousyellow oil of(R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide(7.73 g, 25.2 mmol, 103% yield). ¹H NMR (400 MHz, CDCL₃) δ 1.27 (s, 9H)7.31-7.42 (m, 2H) 7.87 (t, J=7.87 Hz, 1H) 8.83 (s, 1H). LCMS m/z 307.9(M+H)⁺, Rt 1.01 min.

Step 2

To a solution of(R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide(7.73 g, 25.2 mmol) in CH₂Cl₂ (252 mL), cooled to 0° C. (water/ice bath)under nitrogen, was added 3M methyl magnesium bromide (33.7 mL, 101mmol) in Et₂O. Reaction mixture allowed to stir for 30 min at 0° C.,then gradually allowed to warm to room temperature and stirred for 1hour at room temperature. Reaction mixture was cooled to 0° C. thenquenched with the slow addition of a saturated solution of NH₄Cl.Aqueous mixture extracted with EtOAc. Organic phases combined, washedwith water, brine, dried (Na₂SO₄), filtered and concentrated onto silicagel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%)provided(R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(4.93 g, 15.3 mmol, 60% yield) as a white crystalline solid. ¹H NMR (400MHz, CDCL₃) δ 1.20 (s, 9H) 1.56 (d, J=6.70 Hz, 3H) 3.34 (br. s., 1H)4.77-4.87 (m, 1H) 7.19-7.31 (m, 3H). LCMS m/z 324.0 (M+H)⁺, Rt 0.90 min.

Step 3

To a microwave vial with stir bar was added(R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2- (1 g,3.10 mmol), isopropenyl boronic acid pinacol ester (1.51 ml, 8.07 mmol),DME (8 ml), sodium carbonate (7.76 ml, 15.5 mmol) (2.0 M aq) andPdCl₂(dppf). CH₂Cl₂ adduct (0.127 g, 0.155 mmol). Vessel was capped andheated by microwave irradiation for 20 min at 100° C. Reaction mixturewas diluted with a saturated solution of NH₄Cl. The aqueous mixture wasextracted with EtOAc. Organic phases combined, washed with water, brine,dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gelcolumn chromatography (EtOAc/Heptane 50 to 100%) provided(R)—N—((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(830 mg, 2.93 mmol, 94% yield) as a pale brown crystalline. ¹H NMR (400MHz, DMSO) δ 1.08-1.11 (m, 9H) 1.47 (d, J=6.80 Hz, 3H) 2.09 (d, J=0.54Hz, 3H) 4.61-4.71 (m, 1H) 5.14 (t, J=1.32 Hz, 1H) 5.43 (d, J=5.58 Hz,1H) 5.49 (s, 1H) 7.24-7.30 (m, 1H) 7.31-7.36 (m, 1H) 7.41-7.47 (m, 1H).LCMS m/z 284.0 (M+H)⁺, Rt 0.93 min.

Step 4

To a round bottom flask containing(R)—N—((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-(0.37 g, 1.31 mmol) in DCE (13 mL) at 0° C. was added under argondiethylzinc (1.0M in hexanes) (13.1 mL, 13.1 mmol) followed by thedropwise addition of chloroiodomethane (0.95 mL, 13.1 mmol). Reactionmixture allowed to warm to room temperature and stirred for 1 hour.Reaction mixture was cooled to 0° C. whereupon a second addition ofdiethylzinc (1.0M in hexanes) (13.1 mL, 13.1 mmol) took place followedby the addition of chloroiodomethane (0.95 mL, 13.1 mmol). Reactionmixture allowed to warm to room temperature and stirred 18 hours underargon. Reaction mixture was cooled to 0° C. in a ice bath and to thecold reaction mixture was slowly added a saturated solution of NH₄Cl.The aqueous mixture was extracted with EtOAc. Organic phases combined,washed with water, brine, dried (Na₂SO₄), filtered and concentrated ontosilica gel. Silica gel column chromatography (EtOAc/Heptane 20 to 100%)provided a white crystalline of(R)—N—((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(89 mg, 0.299 mmol, 22.92% yield). ¹H NMR (400 MHz, CDCL₃) δ 0.75-0.79(m, 2H) 0.85-0.90 (m, 2H) 1.20 (s, 9H) 1.55 (s, 3H) 1.57 (d, J=6.80 Hz,1H) 3.34 (d, J=5.23 Hz, 1H) 4.75-4.85 (m, 1H) 6.90 (dd, J=12.30, 1.74Hz, 1H) 6.97 (dd, J=8.05, 1.78 Hz, 1H) 7.22 (t, J=7.97 Hz, 1H). LCMS m/z298.1 (M+H)⁺, Rt 1.01 min.

The Intermediates in Table 4k were prepared by a method similar to theone described for the preparation of Intermediate 175.

TABLE 4k

Intermediate 176

Intermediate 177

TABLE 4m Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 4k. Intermediate: Name ¹H NMR (400 MHz) δppm LCMS 176: (R)-2-methyl-N-((S)-1-(6- MS m/z(1-methylcyclopropyl)pyridin-3- 282.1 (M + yl)ethyl)propane-2-sulfinamide H)⁺, Rt 0.48 min. 177: (R)-2-methyl-N-((S)-1-(4-(CDCl₃) 0.71-0.76 (m, 2 H) 0.85- MS m/z (1-methylcyclopropyl) 0.89 (m, 2H) 1.20-1.22 (m, 9 H) 1.41 280.1 (M + phenyl)ethyl) propane-2- (s, 3 H)1.53 (d, J = 6.65 Hz, 3 H) 3.29 H)⁺, Rt 0.98 sulfinamide (d, J = 3.57Hz, 1 H) 4.50-4.57 (m, 1 min. H) 7.21 (s, 2 H) 7.23 (s, 2 H)

Intermediate 178(R)—N—((S)-1-(4-(1-ethoxycyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To a microwave vial with stir bar was added(R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(500 mg, 1.55 mmol) followed by the addition oftributyl(1-ethoxyvinyl)stannane (1.12 g, 3.10 mmol), triethylamine (0.65ml, 4.65 mmol) and PdCl₂(dppf). CH₂Cl₂ adduct (63 mg, 0.078 mmol). Tothe solids was added toluene (10 ml). Vial capped and heated in apreheated sand bath at 100° C. for 1 hour. Reaction mixture was loadedonto silica gel column. Silica gel column chromatography (MeOH/CH₂Cl₂ 0to 10% with 1% NH₄OH buffer) provided(R)—N—((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(498 mg, 1.59 mmol, 102% yield) as a brown viscous oil whichcrystallizes upon standing. ¹H NMR (400 MHz, CDCL₃) δ 1.20 (s, 9H) 1.43(t, J=6.97 Hz, 3H) 1.58 (d, J=6.75 Hz, 3H) 3.35 (d, J=4.74 Hz, 1H) 3.92(q, J=6.96 Hz, 2H) 4.23 (d, J=2.79 Hz, 1H) 4.65 (d, J=2.79 Hz, 1H)4.79-4.89 (m, 1H) 7.16-7.20 (m, 1H) 7.29-7.34 (m, 1H) 7.39 (dd, J=8.07,1.66 Hz, 1H).

Step 2

To a round bottom flask containing(R)—N—((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(0.49 g, 1.56 mmol) and chloroiodomethane (1.14 mL, 15.6 mmol) intoluene (15 mL) at 0° C. under argon was added diethylzinc (1.0M inhexanes) (15.6 mL, 15.6 mmol). Reaction mixture allowed to warm to roomtemperature and stirred for 1 hour. Reaction mixture was cooled to 0° C.in an ice bath and to the cold reaction mixture was slowly added asaturated solution of NH₄Cl. The aqueous mixture was extracted withEtOAc. Organic phases combined, washed with water, brine, dried(Na₂SO₄), filtered and concentrated onto silica gel. Silica gel columnchromatography (MeOH/CH₂Cl₂ 0 to 10%) provided(R)—N—((S)-1-(4-(1-ethoxycyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(145 mg, 0.44 mmol, 28% yield) as a viscous brown oil. ¹H NMR (300 MHz,CDCL₃) δ 0.93-0.99 (m, 2H) 1.14-1.20 (m, 3H) 1.21 (s, 9H) 1.22-1.27 (m,2H) 1.57-1.61 (m, 4H) 3.35 (d, J=4.98 Hz, 1H) 3.45 (q, J=7.07 Hz, 2H)4.77-4.87 (m, 1H) 6.98 (dd, J=7.58, 1.43 Hz, 3H) 7.00-7.03 (m, 4H)7.28-7.32 (m, 1H). LCMS m/z 328.1 (M+H)⁺, Rt 0.95 min.

The Intermediate in Table 4n were prepared by a method similar to theone described for the preparation of Intermediate 178.

TABLE 4n

Intermediate 179

Intermediate 180

Intermediate 181

TABLE 4p Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 4n. Intermediate: Name ¹H NMR (400 MHz) δppm LCMS 179: (R)-N-((S)-1-(2,5-difluoro-4- MS m/z 304.2isopropylphenyl)ethyl)-2- (M + H)⁺, Rt methylpropane-2-sulfinamid 1.04min. 180: (R)-N-((S)-1-(4-bromo-2,5- MS m/z 340.1,difluorophenyl)ethyl)-2- 342.1 (M + methylpropane-2-sulfinamide H)⁺, Rt0.96 min. 181: (R)-N-((S)-1-(6-(1- MS m/z ethoxycyclopropyl)pyridin-3-311.1 (M + yl)ethyl)-2-methylpropane-2- H)⁺, Rt 0.52 sulfinamide min.

Intermediate 182(R)—N—((S)-1-(4-(1-cyanocyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To a microwave vial with a stir bar was added(R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(300 mg, 0.93 mmol), 4-isoxazoleboronic acid pinacol ester (218 mg, 1.12mmol), PdCl₂(dppf).CH₂Cl₂ adduct (76 mg, 0.09 mmol), potassium fluoride(2.7 mL, 1.0 M in water, 2.79 mmol) and finally DMSO (9 mL). Thereaction mixture was degassed with bubbling nitrogen (3 min) and thevial capped and heated in a preheated oil bath at 130° C. for 18 hours.The reaction mixture was diluted with a saturated solution of NH₄Cl andextracted with EtOAc. Organic phases combined, washed with water, brine,dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gelcolumn chromatography (EtOAc/Heptanes 40 to 100%) provided(R)—N—((S)-1-(4-(cyanomethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(136 mg, 0.48 mmol, 52% yield) as a viscous brown oil. ¹H NMR (400 MHz,CDCL₃) δ 1.19 (s, 9H) 1.57 (d, J=6.80 Hz, 3H) 3.39 (d, J=4.35 Hz, 1H)3.74 (s, 2H) 4.81-4.88 (m, 1H) 7.04 (d, J=10.66 Hz, 1H) 7.11 (d, J=7.97Hz, 1H) 7.38 (t, J=7.73 Hz, 1H). LCMS m/z 283.0 (M+H)⁺, Rt 0.72 min.

Step 2

To a scintillation vial containing(R)—N—((S)-1-(4-(cyanomethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-(86 mg, 0.31 mmol) and a stir bar was added toluene (2 mL). To thismixture was then added tetrabutylammonium bromide (19 mg, 0.06 mmol)followed by the addition of NaOH (1.52 ml, 1.0 M (aq), 1.52 mmol) and1,2-dibromoethane (0.11 ml, 1.22 mmol). Vial capped and reaction mixturewas stirred vigorously at room temperature for 18 hours. Whereupon,1,2-dibromoethane (0.11 ml, 1.22 mmol) and tetrabutylammonium bromide(19 mg, 0.06 mmol) were added and reaction mixture allowed to stir anadditional 18 hours. A third addition of 1,2-dibromoethane (0.11 ml,1.22 mmol) was added and the reaction mixture heated to 50° C. for anadditional 18 hours in a preheated aluminum tray. The reaction mixturewas quenched with a saturated solution of NH₄Cl and the aqueous mixtureextracted with EtOAc. Organics combined and washed twice with water,brine, dried (Na₂SO₄), filtered and concentrated. Crude material waspassed through a small plug of silica gel using 10% MeOH:90% DCM toelute product. The solution was concentrated to afford a viscous orangeoil of(R)—N—((S)-1-(4-(1-cyanocyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(23 mg, 0.08 mmol, 24% yield). ¹H NMR (400 MHz, CDCL₃) δ 1.20 (s, 9H)1.38-1.44 (m, 2H) 1.56 (d, J=6.75 Hz, 3H) 1.73-1.79 (m, 2H) 3.37 (d,J=4.45 Hz, 1H) 4.78-4.88 (m, 1H) 6.94 (dd, J=11.35, 1.91 Hz, 1H) 7.09(dd, J=8.07, 1.91 Hz, 1H) 7.34 (t, J=7.90 Hz, 1H). LCMS m/z 309.2(M+H)⁺, Rt 0.83 min.

Intermediate 183(R)—N—((S)-1-(2-fluoro-4-isopropylphenyl)ethyl)-2-methylpropane-2-sulfinamide

To a round bottom flask containing(R)—N—((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(204 mg, 0.72 mmol) and a stir bar was added MeOH (7.2 mL). To thissolution was added palladium on carbon (77 mg, 10%, 0.07 mmol) in MeOH(1 mL). A hydrogen atmosphere was inserted and the resulting reactionmixture stirred at room temperature for 18 hours, at which time morepalladium on carbon was added (300 mg) in MeOH (5 mL). A hydrogenatmosphere was inserted again and the reaction mixture allowed to stiran additional 18 hours at room temperature. The reaction mixture wasfiltered through a syringe filter and concentrated to afford a lightbrown viscous oil of(R)—N—((S)-1-(2-fluoro-4-isopropylphenyl)ethyl)-2-methylpropane-2-sulfinamide(149 mg, 0.52 mmol, 73% yield) which crystallizes upon standing. ¹H NMR(400 MHz, CDCl₃) δ 1.20 (s, 9H) 1.24 (d, J=5.87 Hz, 6H) 1.58 (d, J=6.70Hz, 3H) 2.89 (dt, J=13.79, 6.90 Hz, 1H) 3.35 (d, J=5.04 Hz, 1H)4.76-4.85 (m, 1H) 6.90 (dd, J=12.03, 1.52 Hz, 1H) 6.98 (dd, J=7.90, 1.54Hz, 1H) 7.24 (t, J=7.97 Hz, 1H). LCMS m/z 286.3 (M+H)⁺, Rt 1.01 min.

Intermediate 184(R)—N—((S)-1-(4-cyclopropyl-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

To a microwave vial containing a stir bar was added(R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(100 mg, 0.31 mmol) followed by the addition of potassiumcyclopropyltrifluoroborate (459 mg, 3.10 mmol), cesium carbonate (506mg, 1.55 mmol) and Pd(OAc)₂ (7 mg, 0.03 mmol) anddi(1-adamantyl)-n-butylphosphine (22 mg, 0.06 mmol), toluene (2.6 mL)and finally water (0.5 mL). The vial capped and heated by microwaveirradiation for 20 min at 100° C., followed by thermal heating at 100°C. in a preheated aluminum tray for 18 hours. The reaction mixture wasdiluted with a saturated solution of NH₄Cl. The aqueous mixtureextracted with EtOAc. Organic phases combined, washed with water, brine,dried (Na₂SO₄), filtered and concentrated to afford a yellow crystallineof(R)—N—((S)-1-(4-cyclopropyl-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(116 mg, 0.33 mmol, 106% yield). LCMS m/z 284.0 (M+H)⁺, Rt 0.90 min.

Intermediate 185(R)—N—((S)-1-(6-cyclopropylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

(R)—N—((S)-1-(6-cyclopropylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamideis prepared with a method similar to that used to access Intermediate184. MS m/z 267.1 (M+H)+, Rt 0.44 min.

Intermediate 186(R)—N—((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a two microwave vials with stir bars were added(R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(1.5 g, 4.65 mmol), 1-methyl-4-1H-pyrazoleboronic acid pinacol ester(2.91 g, 13.9 mmol), DME (20 mL), sodium carbonate (11.6 mL, 23.3 mmol,2.0 M aq) and PdCl₂(dppf).CH₂Cl₂ adduct (190 mg, 0.23 mmol) dividedbetween the two vials. The vials were capped and heated by microwaveirradiation for 20 min at 100° C. respectively. The reaction mixturescombined, diluted with a saturated solution of NH₄Cl and EtOAc. Thephases were partitioned and the aqueous phase extracted with EtOAc.Organic phases combined, washed with water, brine, dried (Na₂SO₄),filtered and concentrated onto silica gel. Silica gel columnchromatography (EtOAc/Heptane 40 to 100%) provided a orange crystallineof(R)—N—((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(1.07 g, 3.31 mmol, 71% yield. ¹H NMR (400 MHz, CDCL₃) δ ppm 1.21 (s,9H) 1.60 (d, J=6.80 Hz, 3H) 3.36 (d, J=4.25 Hz, 1H) 3.96 (s, 3H)4.79-4.91 (m, 1H) 7.13 (dd, J=11.69, 1.61 Hz, 1H) 7.23 (dd, J=8.00, 1.64Hz, 1H) 7.30-7.37 (m, 1H) 7.60 (s, 1H) 7.74 (s, 1H). LCMS m/z 324.0(M+H)⁺, Rt 0.74 min.

The Intermediates in Table 4q were prepared by a method similar to theone described for the preparation of Intermediate 186.

TABLE 4q

Intermediate 187

Intermediate 188

Intermediate 189

TABLE 4r Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 4q. Intermediate: Name ¹H NMR (400 MHz) δppm LCMS 187: (R)-2-methyl-N-((S)-1-(4- MS m/z (1-methyl-1H-pyrazol-4-306.0 (M + yl)phenyl)ethyl)propane-2- H)⁺, Rt 0.71 sulfinamide min. 188:(R)-N-((S)-1-(4-(1,5- MS m/z dimethyl-1H-pyrazol-4- 320.0 (M +yl)phenyl)ethyl)-2- H)⁺, Rt 0.72 methylpropane-2-sulfinamide min. 189:(R)-N-((S)-1-(2-fluoro-4- (DMSO) 1.10 (s, 9 H) 1.47 (d, J = 6.75 MS m/z(1H-pyrazol-4-yl)phenyl)ethyl)- Hz, 3 H) 4.60-4.70 (m, 1 H) 5.41 (d,310.0 (M + 2-methylpropane-2-sulfinamide J = 5.48 Hz, 1 H) 7.38-7.44 (m,3 H) H)⁺, Rt 0.67 7.96 (br. s., 1 H) 8.23 (br. s., 1 H) min. 12.97 (br.s., 1 H)

Intermediate 190(R)—N—((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To a oven dried round bottom flask with stir bar was added2-fluoro-4-(trifluoromethyl)benzaldehyde (5 g, 26.0 mmol),(R)-2-methylpropane-2-sulfinamide (3.47 g, 28.6 mmol) and DCE (52 mL).To this mixture was then added copper (II) sulfate (6.23 g, 39.0 mmol).The reaction mixture was heated in a preheated oil bath at 55° C. for 18hours. The reaction mixture was filtered through a pad celite, washingthe solids with DCE. The filtrate was concentrated to afford a viscousgreen oil of (R,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (7.3 g, 24.7 mmol, 95% yield). Material was takenonto next step without further purification. ¹H NMR (400 MHz, CDCl₃) δppm 1.29 (s, 9H) 7.44 (d, J=10.08 Hz, 1H) 7.51 (d, J=8.27 Hz, 1H) 8.13(t, J=7.46 Hz, 1H) 8.92 (s, 1H). LCMS m/z 296.0 (M+H)⁺, Rt 1.02 min.

Step 2

To a solution of(R,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide(7.3 g, 24.7 mmol) in CH₂Cl₂ (247 mL) cooled to 0° C. (water/ice bath)under nitrogen, was added 3M methyl magnesium bromide (33 mL, 99 mmol)in Et₂O. Reaction mixture allowed to stir for 30 min at 0° C., thengradually allowed to warm to room temperature and stirred for 1 hour atroom temperature. Reaction mixture was cooled to 0° C. then quenchedwith the slow addition of a saturated solution of NH₄Cl. Aqueous mixtureextracted with EtOAc. Organic phases combined, washed with water, brine,dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gelcolumn chromatography (EtOAc/Heptane 40 to 100%) provided(R)—N—((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(4.68 g, 15.0 mmol, 61% yield) as a white crystalline solid. ¹H NMR (400MHz, CDCL₃) δ 1.22 (s, 9H) 1.60 (d, J=6.80 Hz, 3H) 3.38 (d, J=4.01 Hz,1H) 4.87-4.97 (m, 1H) 7.33 (d, J=10.32 Hz, 1H) 7.39-7.45 (m, 1H)7.49-7.55 (m, 1H). LCMS m/z 312.0 (M+H)⁺, Rt 0.92 min.

Intermediate 191(R)—N—((S)-1-(6-tert-butylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

(R)—N—((S)-1-(6-tert-butylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamideis prepared with methods similar to those used to prepare Intermediate190. ¹H NMR (400 MHz, CDCl₃) δ 1.22 (s, 9H) 1.37 (s, 9H) 1.57 (d, J=6.75Hz, 3H) 3.31 (d, J=3.37 Hz, 1H) 4.56-4.65 (m, 1H) 7.32 (d, J=8.22 Hz,1H) 7.57 (dd, J=8.24, 2.23 Hz, 1H) 8.54 (d, J=2.05 Hz, 1H). MS m/z 283.1(M+H)+, Rt 0.51 min.

Intermediate 192 (S)-tert-butyl1-(3-chloro-4-(cyclopentylcarbamoyl)phenyl)ethyl carbamate

Step 1

To a round bottom flask with stir bar was added 4-((S)-1aminoethyl-2-chlorobenzoic acid HCl salt (1.05 g, 4.45 mmol) followed bythe addition of THF (40 mL). To this solution was added DIEA (1.86 ml,10.7 mmol). The reaction mixture becomes cloudy white followed by theaddition of di-tert-butyl dicarbonate (1.07 g, 4.89 mmol). Resultingreaction mixture allowed to stir for 18 hours at room temperature. Atwhich time the reaction mixture was then heated to 60° C. for 2 hours ina oil bath. Di-tert-butyl dicarbonate (1.07 g, 4.89 mmol) and NMP (20ml) were then added and the resulting reaction mixture allowed to stirfor 2 hours at 60° C. Volatiles were removed. The resulting oil wasdiluted with a saturated solution of NH₄Cl and the aqueous mixtureextracted with EtOAc. The organic phases combined, washed twice withwater, brine, dried (Na₂SO₄), filtered and concentrated to a viscousyellow oil of (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-chlorobenzoicacid (2.32 g, 6.19 mmol, 139% yield) which contains some excessdi-tert-butyl dicarbonate and NMP. LCMS m/z 284.9 (M+H)⁺ (carboxylicacid fragment+CH₃CN adduct), Rt 0.75 min.

Step 2

To a round bottom flask with stir bar was added(S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-chlorobenzoic acid (450 mg,1.20 mmol), cyclopentylamine (355 μL, 3.60 mmol), EDC HCl (460 mg, 2.40mmol), 1-hydroxy-7-aza-benzotriazole (229 mg, 1.68 mmol) and DMF (6 mL).To this mixture was then added DIEA (629 μL, 3.60 mmol). Reactionmixture was allowed to stir at room temperature for 18 hours. Thereaction mixture was diluted with water and extracted with EtOAc. Theorganic phases were combined, washed with twice with water, brine, dried(Na₂SO₄), filtered and concentrated to a brown crystalline of(S)-tert-butyl 1-(3-chloro-4-(cyclopentylcarbamoyl)phenyl)ethylcarbamate(476 mg, 1.17 mmol, 97% yield). LCMS m/z 367.0 (M+H)⁺, Rt 0.90 min.

The Intermediates in Table 4s were prepared by a method similar to theone described for the preparation of Intermediate 192.

TABLE 4s

Inter- mediate 193

Inter- mediate 194

TABLE 4t Chemical name and LCMS signal for each intermediate listed inTable 4s. Intermediate: Name LCMS 193: (S)-tert-butyl 1-(3-chloro-4- MSm/z (cyclohexyl carbamoyl) phenyl) 381.1 (M + ethylcarbamate H)⁺, Rt0.96 min. 194: tert-butyl (S)-1-(3-chloro-4- MS m/z((1r,4S)-4-hydroxycyclohexyl 391.1 (M + carbamoyl)phenyl)ethylcarbamateH)⁺, Rt 0.71 min.

Intermediate 195 (S)-tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate

A slurry of (S)-3-(1-aminoethyl)phenol (1.188 g, 6.84 mmol) and Boc₂O(1.747 mL, 7.53 mmol) in DCM (17.10 mL) was stirred at room temperatureunder N₂ while slowly adding DIEA (1.434 mL, 8.21 mmol). The initiallyinsoluble starting materials slowly dissolve. The solution was stirredat room temperature for 16 hours and then concentrated. The oily residuewas re-dissolved in EtOAc and washed with Na₂CO₃ saturated, followed bybrine. The original aqueous layer was re-extracted with EtOAc, which wasthen washed with brine and combined with the previous EtOAc batch. Thecombined organics were dried over Na₂SO₄, filtered and concentrated to2.4 g crude clear yellowish oil which was purified by silica gel columnchromatography (EtOAc/Heptane 0 to 30%), yielding (S)-tert-butyl1-(3-hydroxyphenyl)ethylcarbamate as a clear colourless oil, whichsolidifies upon sitting (1.79 g, 7.55 mmol, 110% yield). ¹H NMR (400MHz, CDCL₃) δ 1.44 (br. s., 12H) 4.08-4.18 (m, 1H) 4.76 (br. s., 1H)6.72 (dd, J=7.46, 1.83 Hz, 1H) 6.78 (br. s., 1H) 6.88 (br. s., 1H)7.16-7.24 (m, 1H). LCMS m/z 223.0/182.0 (the parent not observed, justthe Boc fragments) (M+H)⁺, Rt 0.71 min.

Intermediate 196 (S)-1-(3-(cyclopentyloxy)phenyl)ethanaminehydrochloride

Step 1: Mitsunobu A

To a solution of (S)-tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate (107.5mg, 0.453 mmol), PPh₃ (238 mg, 0.906 mmol) and cyclopentanol (0.164 ml,1.812 mmol) in THF (2 ml) at room temperature was added DEAD (0.143 ml,0.906 mmol) dropwise under N₂. The resulting yellow solution was stirredfor 4 hours and then concentrated. The viscous yellow oil wasre-dissolved in DMSO and purified by reverse phase HPLC. The combinedproduct fractions were desalted by addition of equal amount of EtOAc andabout 250 mg Na₂CO₃ in a separatory funnel. The phases were separatedand the organic washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to yield (S)-tert-butyl1-(3-(cyclopentyloxy)phenyl)ethylcarbamate (75.1 mg, 0.246 mmol, 54.3%yield) as a white solid film. LCMS m/z 291.1/250.0 (the parent notobserved, just the Boc fragments) (M+H)⁺, Rt 1.07 min.

Step 2

(S)-tert-butyl 1-(3-(cyclopentyloxy)phenyl)ethylcarbamate (75.1 mg,0.246 mmol) was dissolved in 4M HCl in dioxane (1 ml, 4.00 mmol) and theresulting mixture was allowed to sit for 1 hour, then concentrated toyield (S)-1-(3-(cyclopentyloxy)phenyl)ethanamine as an HCl salt (yieldassumed quantitative). LCMS m/z 206.1 (M+H)⁺, Rt 0.61 min.

Intermediate 197 (S)-1-(3-(cyclohexyloxy)phenyl)ethanamine hydrochloride

Step 1: Mitsunobu B

To a solution of (S)-tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate (100mg, 0.421 mmol), cyclohexanol (0.180 ml, 1.686 mmol) and PPh₃ (221 mg,0.843 mmol) in THF (2 ml), was added DEAD (0.133 ml, 0.843 mmol)dropwise, under N₂, at room temperature. The resulting yellow solutionwas stirred for 3 hours, at which point another batch of cyclohexanol(0.180 ml, 1.686 mmol), PPh₃ (221 mg, 0.843 mmol), and 10 min later DEAD(0.133 ml, 0.843 mmol), was added at room temperature. The reactionmixture was stirred for 16 hours and then concentrated. The crude clearoil was re-dissolved in DMSO and purified by reverse phase HPLC. Thecombined product fractions were desalted by addition of equal amount ofEtOAc and about 250 mg Na₂CO₃ in a separatory funnel. The phases wereseparated and the organic washed with brine, dried over MgSO₄, filteredand concentrated in vacuo to yield (S)-tert-butyl1-(3-(cyclohexyloxy)phenyl)ethylcarbamate (74.1 mg, 0.232 mmol, 55.0%yield) as a clear colourless film. LCMS m/z 305.0/264.0 (the parent notobserved, just the Boc fragments) (M+H)⁺, Rt 1.12 min.

Step 2

(S)-tert-butyl 1-(3-(cyclohexyloxy)phenyl)ethylcarbamate (74.1 mg, 0.232mmol) was dissolved in 4M HCl in dioxane (1 ml, 4.00 mmol) and theresulting mixture was allowed to sit for 1 hour, then concentrated toyield (S)-1-(3-(cyclohexyloxy)phenyl)ethanamine as an HCl salt (yieldassumed quantitative). LCMS m/z 220.1 (M+H)⁺, Rt 0.66 min.

The Intermediates in Table 4v were prepared using either the methoddescribed for the preparation of Intermediate 196 or Intermediate 197.

TABLE 4v Intermediate: Name Structure LCMS 198: (S)-1-(3-(cyclopentyloxy)phenyl)ethanamine

MS m/z 206.1 (M + H)⁺, Rt 0.61 min. 199: (S)-1-(3-(cyclohexyloxy)phenyl)ethanamine

MS m/z 220.1 (M + H)⁺, Rt 0.66 min. 200: (S)-1-(3-(cycloheptyloxy)phenyl)ethanamine

MS m/z 234.1 (M + H)⁺, Rt 0.73 min. 201: (S)-1-(3-isopropoxyphenyl)ethanamine

MS m/z 180.1 (M + H)⁺, Rt 0.50 min. 202: (S)-1-(3-isobutoxyphenyl)ethanamine

MS m/z 194.1 (M + H)⁺, Rt 0.61 min. 203: (S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethanamine

MS m/z 208.1 (M + H)⁺, Rt 0.41 min. 204: (1S)-1-(3-(tetrahydro-2H-pyran-3-yloxy)phenyl)ethanamine

MS m/z 222.1 (M + H)⁺, Rt 0.46 min.

Intermediate 205 (S)-1-(3-phenoxyphenyl)ethanamine

Into a 20 ml microwave vial was weighted 1-(pyridin-2-yl)propan-2-oneligand (90 mg, 0.665 mmol), phenol (407 mg, 4.32 mmol), CuBr (47.7 mg,0.332 mmol) and Cs₂CO₃ (2166 mg, 6.65 mmol). To the mixture was addedDMSO (5 ml) and (S)-1-(3-bromophenyl)ethanamine (0.5 ml, 3.32 mmol). Thetube was flushed with N₂, capped, and the black mixture heated in theoil bath at 90° C. for 18 hours. The heterogenous mixture was dilutedwith EtOAc and filtered through a glass-fritted funnel, eluting withEtOAc and another 5 mls of DMSO. The volatiles were then removed invacuo and the crude brown liquid was filtered through 1 μm PTFE filterand purified by reverse phase HPLC. The combined product fractions weredesalted by addition of equal amount of EtOAc and about 250 mg Na₂CO₃ ina separatory funnel. The phases were separated and the organic washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo toyield (S)-1-(3-phenoxyphenyl)ethanamine (361.5 mg, 1.678 mmol, 50.5%yield) as an amber oil. LCMS m/z 214.1 (M+H)⁺, Rt 0.61 min.

Intermediate 206 (S)-1-(2,3-difluorophenyl)ethanamine

Step 1

To a oven dried round bottom flask with stir bar was added2,3-difluorobenzaldehyde (0.5 g, 3.52 mmol),(R)-2-methylpropane-2-sulfinamide (0.469 g, 3.87 mmol) and DCE (7.04mL). To this mixture was then added Copper (II) Sulfate (0.842 g, 5.28mmol). Reaction mixture heated in a preheated oil bath to 55° C. for 24hours. The reaction mixture was filtered through a celite pad washingsolids with DCE. Combined filtrate was concentrated to afford a viscousyellow oil of(R,E)-N-(2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide (0.8007g, 3.26 mmol, 93% yield). LCMS m/z 246.1 (M+H)+, Rt 0.91 min.

Step 2

To a solution of(R,E)-N-(2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide (0.800g, 3.26 mmol) in DCM (32.6 mL), cooled to 0° C. (water/icebath) underN2, was added 3M MeMgBr (4.35 mL, 13.05 mmol) in diethyl ether. Reactionmixture allowed to stir for 30 min at 0° C. Then gradually allowed towarm to room temperature and stirred for 30 min at room temperature.Reaction mixture was cooled to 0° C. then quenched with the slowaddition of a saturated solution of NH4Cl and diluted with EtOAc. Phasespartitioned aqueous phase extracted with EtOAc and the organic layerscombined washed with water, brine, dried with MgSO4, filtered andconcentrated to afford(R)—N—((S)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(0.7868 g, 3.01 mmol, 92% yield) as yellow solid. LCMS m/z 262.0 (M+H)+,Rt 0.70 min.

Step 3

To a round bottom flask containing(R)—N—((S)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(786.8 mg, 3.01 mmol) was added Dioxane (10.000 mL). To this solutionwas added HCl in dioxane 4.0M (1.505 mL, 6.02 mmol) and the solution wasallowed to stir 15 min at room temperature. The reaction mixture wasconcentrated, dissolved in Et2O 10 ml, and concentrated again. Et2O wasagain added and resulting mixture sonnicated and a solid material wasfiltered and dried to afford (S)-1-(2,3-difluorophenyl)ethanamine(0.4213 g, 2.176 mmol, 72.3% yield) as a white crystalline HCl salt. ¹HNMR (400 MHz, D20) d ppm 1.55 (d, J=6.99 Hz, 3H) 4.71 (q, J=6.96 Hz, 1H)7.10-7.26 (m, 3H); LCMS m/z 158.0 (M+H)+, Rt 0.37 min.

Intermediate 207 (S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethanamine

Step 1: Preparation of 1-bromo-4-(difluoromethyl)-2-fluorobenzene

A mixture of 4-bromo-3-fluorobenzaldehyde (2.03 g, 10 mmol) and(diethylamino)sulfur trifluoride (DAST; 1.32 mL, 10 mmol) is heatedcarefully until exothermic reaction occurs, then heated at 60° C. for 15min, and allowed to cool to room temperature. The mixture was dilutedwith DCM (20 mL) and poured into ice/water (30 mL). The mixture wasneutralized with NaHCO₃ to ˜pH 8. The separated aqueous layer wasextracted with DCM (20 mL). The combined organic layers were dried overNa₂SO₄, filtered off, and concentrated under reduced pressure. Theresidue was purified by column chromatography [SiO₂, 40 g, heptane/ethylacetate], providing 1-bromo-4-(difluoromethyl)-2-fluorobenzene (0.845 g)as a clear colorless oil.

Step 2: Preparation of 4-(difluoromethyl)-2-fluorobenzaldehyde

To a solution of 1-bromo-4-(difluoromethyl)-2-fluorobenzene (311 mg,1.382 mmol) in THF (2.99 mL) was added butyllithium (1.6M solution inhexanes; 0.881 mL, 1.410 mmol) over ˜5 min at −78° C. The reactionmixture was stirred for 30 min at −78° C. then DMF (0.161 mL, 2.073mmol) was added dropwise over ˜1 min. Stirring was continued for 20 min.The reaction mixture was quenched with aqueous 1M HCl solution/MeOH(2:1, 3 mL) and allowed to warm to room temperature. The mixture wasdiluted with 5 mL of water. The separated aqueous layer was with ether(5 mL). The combined organic layers were washed with 1M aqueous NaOHsolution (10 mL) and saturated brine (10 mL), dried over MgSO₄, filteredoff and concentrated under reduced pressure. Repeated reaction with 420mg of 1-bromo-4-(difluoromethyl)-2-fluorobenzene and combined crudematerials for purification. The crude material was purified by columnchromatography [SiO₂, 24 g, heptane/ethyl acetate], providing4-(difluoromethyl)-2-fluorobenzaldehyde (162.8 mg) as a yellow oil.

Step 3: Preparation of(R,E)-N-(4-(difluoromethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide

To a mixture of 4-(difluoromethyl)-2-fluorobenzaldehyde (162 mg, 0.930mmol) and (R)-2-methylpropane-2-sulfinamide (124 mg, 1.023 mmol) in DCE(3 mL) was added copper sulfate (223 mg, 1.396 mmol). Reaction mixturewas heated in a preheated oil bath to 55° C. for 38 hours. The mixturewas allowed to cool to room temperature, filtered through a pad ofcelites and washed with DCE. Combined filtrates were concentrated underreduced pressure to afford(R,E)-N-(4-(difluoromethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide(266 mg) as a yellow oil, which was used without further purification.LCMS m/z 278.1 (M+H)⁺, Rt 0.98 min.

Step 4: Preparation of(R)—N—((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of(R,E)-N-(4-(difluoromethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide(266 mg, 0.959 mmol) in DCM (9.6 mL) was added methylmagnesium bromide(3M in diethylether; 1.20 mL) at 0° C. The reaction mixture was allowedto stir for 30 min at 0° C., gradually allowed to warm to roomtemperature and stirred for 1 hour at room temperature. The mixture wascooled to 0° C., and carefully quenched with saturated aqueous NH₄Clsolution (3 mL). The separated aqueous phase was extracted with DCM. Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered off and concentrated under reduced pressure. The crudematerial was purified by column chromatography [SiO₂, 40 g,heptane/ethyl acetate], providing(R)—N—((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(160.5 mg) as a white solid. LCMS m/z 294.5 (M+H)⁺, Rt 0.85 min.

Step 5: Preparation of(5)-1-(4-(difluoromethyl)-2-fluorophenyl)ethanamine

To(R)—N—((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(160 mg, 0.545 mmol) was added 4M HCl in dioxane (409 μL) to give ayellow solution. The resulting mixture was stirred at room temperaturefor ˜1 hour. To the mixture was added slowly diethylether (˜20 mL). Thesolids were filtered off, suspended in diethylether, filtered off andrinsed with diethylether, dried under reduced pressure providing(S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethanamine (103 mg) as anoff-white solid, which was used without further purification. LCMS m/z190.1 (M+H)⁺, Rt 0.42 min.

Intermediate 208 (S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethanamine

Step 1: Preparation of 4-(pyrimidin-5-yloxy)benzaldehyde

To a solution of pyrimidin-5-ol (500 mg, 5.20 mmol) in DMF (5.20 mL)under argon was added 4-fluorobenzaldehyde (0.558 mL, 5.20 mmol), sodiummethanesulfinate (133 mg, 1.30 mmol), and potassium carbonate (1.079 g,7.81 mmol). The reaction mixture was heated at 120° C. for 3 hour. Themixture was allowed to cool to room temperature and was diluted withwater (25 mL). The mixture was extracted with EtOAc (2×25 mL). Thecombined organic layers were washed with brine (2×50 mL), dried oversodium sulfate, filtered off and concentrated under reduced pressure.The residue was purified by column chromatography [SiO₂, 24 g,heptane/ethyl acetate], providing 4-(pyrimidin-5-yloxy)benzaldehyde (666mg) as a yellow solid. LCMS m/z 201.0 (M+H)⁺, Rt 0.52 min.

Step 2: Preparation of(R,E)-2-methyl-N-(4-(pyrimidin-5-yloxy)benzylidene)propane-2-sulfinamide

A mixture of 4-(pyrimidin-5-yloxy)benzaldehyde (666 mg, 3.33 mmol),(R)-(+)-tert-butanesulfinamide (450 mg, 3.71 mmol) and copper sulfate(796 mg, 4.99 mmol) in anhydrous in dichloroethane (7.648 mL) and underargon was heated at 55° C. for ˜21 hours. The reaction mixture wasallowed to cool to room temperature. The slurry was filtered through acelite pad, eluted with DCM (5×10 mL). The combined filtrates wereconcentrated under reduced pressure and the resulting yellowish oil waspurified by column chromatography [SiO₂, 24 g, heptane/ethyl acetate]providing(R,E)-2-methyl-N-(4-(pyrimidin-5-yloxy)benzylidene)propane-2-sulfinamide(836 mg) as a pale viscous oil. LCMS m/z 304.0 (M+H)⁺, Rt 0.79 min.

Step 3: Preparation of2-methyl-N—((S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethyl)propane-2-sulfinamide

A solution of(R,E)-2-methyl-N-(4-(pyrimidin-5-yloxy)benzylidene)propane-2-sulfinamide(830 mg, 2.74 mmol) in DCM (6.72 mL) was cooled to −40° C. To thesolution was added methylmagnesium bromide (3M in diethylether; 1.81 mL)dropwise over 10 min. Additional DCM (5 mL) were added to retainstirring. The yellow suspension was stirred at −40° C. for ˜30 min whilewarming to −20° C. The mixture was cooled to −40° C. and additionalmethylmagnesium bromide (3M in diethylether; 1.8 mL) was added. Thesuspension was stirred for ˜3 hour while slowly warming to −20° C. Themixture was cooled to ˜−40° C., and additional methylmagnesium bromide(3M in diethylether; 0.4 mL) was added. The suspension was stirred for30 min and allowed to warm to −10° C. The mixture was quenched slowlyover 10 min with saturated aqueous NH₄Cl solution (10 mL). The mixturewas diluted with saturated aqueous NH₄Cl solution (30 mL) and water (15mL). The separated aqueous phase was extract with DCM (2×75 mL). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered off and concentrated under reduced pressure. Theresidue was purified by column chouromatography [SiO₂, 40 g,heptane/ethyl acetate followed by 5% MeOH in EtOAc] providing2-methyl-N—((S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethyl)propane-2-sulfinamide(55 mg; purity ˜87%) as an off-white solid. LCMS m/z 320.0 (M+H)⁺, Rt0.69 min.

Step 4: Preparation of (5)-1-(4-(pyrimidin-5-yloxy)phenyl)ethanamine

To2-methyl-N—((S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethyl)propane-2-sulfinamide(55 mg, 0.172 mmol) was added 4M HCl in dioxane (800 μL, 3.20 mmol) togive a white suspension. This resulting mixture was stirred at roomtemperature for ˜35 min and concentrated under reduced pressure toprovide crude (S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethanamine (44 mg) asits HCl salt, which was used without further purification. LCMS m/z217.1 (M+H)⁺, Rt 0.37 min.

Intermediate 209 5-chloro-6-(1,1-difluoroethyl)nicotinaldehyde

Step 1: Preparation of ethyl 5,6-dichloronicotinate

To a solution of 5,6-dichloronicotinic acid (20.01 g, 104 mmol) in EtOH(500 mL) at 20° C. was added chlorotrimethylsilane (132 mL, 1042 mmol).The reaction was stirred for 72 hours. The reaction mixture was thenconcentrated and diluted with EtOAc (500 mL), and washed with saturatedNaHCO₃ (2×100 mL) and brine (100 mL). The organic was then dried(Na₂SO₄) and concentrated under reduced pressure to give final crudeproduct (21.25 g). LCMS m/z 220.1 (M+H)⁺, Rt 0.94 min.

Step 2: Preparation of ethyl 6-acetyl-5-chloronicotinate

To a suspension of ethyl 5,6-dichloronicotinate (5.26 g, 23.90 mmol) andtetraethylammonium-chloride (11.88 g, 71.7 mmol) in MeCN (50 mL) wasadded tributyl(1-ethoxyvinyl)stannane (9.50 g, 26.3 mmol) andPdCl₂(PPh₃)₂ (0.671 g, 0.956 mmol). The reaction was sealed, heated at80° C. for 5 hours. A dark color clear solution resulted. The reactionmixture was then cooled to 20° C., concentrated and diluted with EtOAc(200 mL), and washed with water (50 mL) and brine (50 mL). The organicwas then dried (Na₂SO₄) and concentrated to give crude ethyl5-chloro-6-(1-ethoxyvinyl)nicotinate. The residue was then dissolved inTHF (100 mL) and HCl (20 mL, 3M in H₂O) was added. The reaction mixturewas stirred at 20° C. for 5 hours, and saturated NaHCO₃ solution wasadded until pH=8. The mixture was then diluted with EtOAc (200 mL) andwater (50 mL). The phases were separated and the aqueous layer wasextracted with EtOAc (2×50 mL). The combined organics was washed withbrine (20 mL), dried (Na₂SO₄) and concentrated to afford the desiredproduct (3.56 g). LCMS m/z 228.5 (M+H)⁺, Rt 0.83 min.

Step 3: Preparation of ethyl 5-chloro-6-(1,1-difluoroethyl)nicotinate

To a solution of ethyl 6-acetyl-5-chloronicotinate (3.01 g, 13.22 mmol)in CHCl3 (7 mL) was added DAST (5.20 mL, 39.7 mmol) and ethanol (0.061g, 1.32 mmol). The reaction was sealed, heated at 60° C. for 24 hours. Adark color clear solution resulted. The reaction mixture was then cooledto 20° C., and added cautiously with cold concentrated NaHCO₃ aqueoussolution (50 mL). The aqueous layer was extracted with DCM (2×100 mL).The combined organic was then dried (Na₂SO₄) and concentrated. Theresidue was purified via silica gel flash chromatography (0-20percentEtOAc-Hexanes) to afford the desired product as yellow oil (2.88 g).LCMS m/z 250.1 (M+H)⁺, Rt 0.99 min.

Step 4: Preparation of(5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl)methanol

To a solution of ethyl 5-chloro-6-(1,1-difluoroethyl)nicotinate (2.68 g,10.74 mmol) in Et₂O (40 mL) was added LiBH₄ (0.351 g, 16.10 mmol),followed by dropwise addition of methanol (0.653 mL, 16.10 mmol). Thereaction was refluxed at 40° C. for one hour. The reaction mixture wasthen cooled to 0° C., and quenched with HCl (1M) until pH=2 for aqueouslayer. The phases were separated and the aqueous layer was extractedwith DCM (3×50 mL). The organic was then dried (Na₂SO₄) and concentratedunder reduced pressure to give final crude product (2.12 g). LCMS m/z208.0 (M+H)⁺, Rt 0.63 min.

Step 5: Preparation of 5-chloro-6-(1,1-difluoroethyl)nicotinaldehyde

To a solution of (5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl)methanol(2.12 g, 10.21 mmol) in DCM (100 ml) was added PCC (3.30 g, 15.32 mmol).The reaction was stirred at 20° C. for 3 hours. A dark color suspensionresulted. LCMS showed clean conversion to the product. The reactionmixture was then filtered through a pad of celite, and washed with DCM(200 mL). The filtrate was then concentrated to give crude product (1.78g). LCMS m/z 224.0 (M+H₂O+H)⁺, Rt 0.72 min.

Intermediate 210 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinaldehyde

Step 1: Preparation of ethyl5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate

To a solution of ethyl 5,6-dichloronicotinate (6.28 g, 28.5 mmol) and2,2,2-trifluoroethanol (2.71 ml, 37.1 mmol) in THF (90 ml) at −73° C.was added NaHMDS (37.1 ml, 37.1 mmol). The reaction was stirred at −73°C. for 30 minutes, then at 0° C. for 5 hours. The reaction was quenchedwith 30 mL saturated NH₄Cl solution. The reaction mixture was thenpoured into 50 mL brine and phases were separated. The aqueous layer wasextracted with DCM (2×100 mL). The combined organics were dried (Na₂SO₄)and concentrated. Silica gel chromatography with 100% heptane to 30%EtOAc in heptane provided final product (7.51 g). LCMS m/z 284.1 (M+H)⁺,Rt 1.07 min.

Step 2: Preparation of(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol

To a solution of ethyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate(7.51 g, 26.5 mmol) in Et2O (200 mL) was added LiBH₄ (0.865 g, 39.7mmol), followed by drop wise addition of methanol (1.611 ml, 39.7 mmol).The reaction was refluxed at 40° C. for one hour. The reaction mixturewas then cooled to 0° C., and quenched with HCl (1M) until pH=2 foraqueous layer. The phases were separated and the aqueous layer wasextracted with DCM (3×200 mL). The organic was then dried (Na₂SO₄) andconcentrated under reduced pressure to give final crude product (6.31g). LCMS m/z 242.1 (M+H)⁺, Rt 0.77 min.

Step 3: Preparation of 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinaldehyde

To a solution of(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (4.00 g, 16.56mmol) in EtOAc (15 mL) was added manganese(IV) oxide (16.93 g, 166mmol). The reaction was heated with microwave at 120° C. for 30 minutes.The mixture was then filtered through a pad of celite, and rinsed withEtOAc. The filtrated was concentrated to give crude product (3.38 g).

The intermediates in Table 4w were prepared with procedures similar tothose used to prepare Intermediate 210 and 192.

TABLE 4w Intermediate: Name Structure LCMS 211:(R)-N-((S)-1-(5-chloro-6- (1,1-difluoroethyl)pyridin-3-yl)ethyl)-2-methylpropane-2- sulfinamide

MS m/z 325.2 (M + H)⁺, Rt 0.85 min. 212: (R)-N-((S)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)-2-methylpropane-2-sulfinamide

MS m/z 359.1 (M + H)⁺, Rt 0.95 min.

Intermediate 213(S)-3-(2-((S)-1-(4-(chloromethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

To a solution of(S)-3-(2-((S)-1-(4-(hydroxymethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one(71 mg, 0.2 mmol) in DCM (2 mL) was added methanesulfonyl chloride (27mg, 0.24 mmol) and DIPEA (0.070 mL, 0.4 mmol). The solution was stirredfor 16 h at room temperature then washed with water and brine. Afterseparation, the organic phase was dried over Na₂SO₄, filtered andconcentrated. The crude product was used to next step without furtherpurification. MS m/z 373.4 (M−H).

Intermediate 214 tert-butyl3-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzyl)-3,8-diazabicyclo[4.2.0]octane-8-carboxylate

Title compound was prepared as a white solid (64 mg, 58.1% yield), withprocedures similar to those used to prepare Intermediate 128, bututilizing4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzaldehydeand tert-butyl 3,8-diazabicyclo[4.2.0]octane-8-carboxylate.

¹H NMR (400 MHz, CDCl3) δ 8.17 (dd, J=5.9, 0.9 Hz, 1H), 7.42 (d, J=5.7Hz, 1H), 7.28-7.23 (m, 4H), 5.39 (br s, 1H), 5.02 (br s, 1H), 4.62-4.59(m, 1H), 4.28 (t, J=8.7 Hz, 1H), 4.21 (dd, J=9.0, 3.2 Hz, 2H), 3.89 (td,J=7.7, 1.9 Hz, 1H), 3.54-3.50 (m, 2H), 3.03 (d, J=12.2 Hz, 1H),2.65-2.60 (m, 1H), 2.54-2.40 (m, 2H), 2.10 (br s, 1H), 1.99-1.88 (m,1H), 1.79-1.72 (m, 1H), 1.65 (br s, 1H), 1.52 (dd, J=6.8, 1.9 Hz, 3H),1.38 (t, J=7.7 Hz, 9H), 0.71 (br s, 3H), 0.66 (br s, 3H). MS m/z 569.1(M+H).

Intermediate 215 tert-butyl1-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzyl)piperidin-4-ylcarbamate

Title compound was prepared as a white solid (32 mg, 59% yield), withprocedures similar to those used to prepare Intermediate 128, bututilizing4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzaldehydeand tert-butyl piperidin-4-ylcarbamate. MS m/z 539.4 (M+H).

EXAMPLES Example 1(S)-5,5-dimethyl-4-phenyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one

A solution of(S)-3-(2-chloropyrimidin-4-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one(33.9 mg, 0.112 mmol) and (S)-(−)-1-phenylethanamine (0.15 mL, 1.2 mmol,10 equiv) in DMSO (1 mL) was heated at 110° C. for 140 min. The reactionmixture was diluted with EtOAc (8 mL) and washed with water (30 mL).After separation, the aqueous phase was extracted with EtOAc (3×8 mL).Combined organics were dried over Na₂SO₄, filtered and concentrated.Silica gel column chromatography (EtOAc/Heptane 10 to 50%) provided(S)-5,5-dimethyl-4-phenyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one (37.0 mg, white solid) in 85% yield. ¹H NMR (400 MHz,CD₃OD) δ 8.06 (d, J=5.8 Hz, 1H), 7.43 (d, J=5.8 Hz, 1H), 7.31-7.24 (m,3H), 7.19-7.11 (m, 5H), 7.01 (br s 2H), 5.48 (s, 1H), 4.86-4.80 (m, 1H),1.65 (s, 3H), 1.43 (d, J=7.0 Hz, 3H), 0.98 (s, 3H); HRMS(B) m/z 389.1987(M+H)⁺.

Alternative Procedure Example 113(S)-3-(2-((S)-1-(4-hydroxyphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(42 mg, 0.17 mmol), (S)-4-(1-aminoethyl)phenol hydrochloride (107 mg,0.616 mmol, 3.5 equiv) and iPr₂Net (0.121 mL, 0.695 mmol, 4.0 equiv) inDMSO (1 mL) was heated at 110° C. for 3 h and at 130° C. for additional2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed withwater (30 mL). After separation, the aqueous phase was extracted withEtOAc (3×8 mL). Combined organics were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 80%)provided(S)-3-(2-((S)-1-(4-hydroxyphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one(3 mg) in 5% yield. ¹H NMR (400 MHz, CD₃OD) δ 8.11 (d, J=5.8 Hz, 1H),7.33 (d, J=5.8 Hz, 1H), 7.12 (d, J 8.1 Hz, 2H), 6.72-6.68 (m, 2H), 4.95(q, J=6.9 Hz, 1H), 4.69-4.65 (m, 1H), 4.35-4.28 (m, 2H), 1.47 (d, J=7.1Hz, 3H), 0.75 (br s, 3H), 0.62 (br s, 3H); HRMS(B) m/z 343.1776 (M+H)⁺.

The compounds in Table 5 were prepared using methods similar to thosedescribed for the preparation of Examples 1 and 113.

TABLE 5

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

TABLE 6 Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 5. ¹H NMR (400 MHz, CD₃OD) δ ppm Example: Name(other solvents described) LCMS 1: (S)-5,5-dimethyl-4- 8.06 (d, J = 5.8Hz, 1 H), 7.43 (d, J = 5.8 HRMS(B) phenyl-3-(2-((S)-1- Hz, 1 H),7.31-7.24 (m, 3 H), 7.19-7.11 m/z phenylethylamino)pyrimidin- (m, 5 H),7.01 (br s 2 H), 5.48 (s, 1 H), 4.86- 389.1987 4-yl)oxazolidin-2-one4.80 (m, 1 H), 1.65 (s, 3 H), 1.43 (d, J = (M + H)⁺ 7.0 Hz, 3 H), 0.98(s, 3 H) 2: 3-(2-(1- 8.06 (d, J = 6.1 Hz, 1 H), 7.37-7.26 (m, 5 HRMS(B)phenylethylamino)pyrimidin- H), 7.22-7.15 (m, 1 H), 5.04 (q, J = 6.9 m/z4-yl)oxazolidin-2-one Hz, 1 H), 4.43 (sxt, J = 8.2 Hz, 2 H), 4.17284.1275 (td, J = 9.8, 7.1 Hz, 1 H), 3.92 (br s, 1 H), M⁺ 1.50 (d, J =7.1 Hz, 3 H) 3: (S)-4-isopropyl-3-(2- 8.12 (d, J = 5.6 Hz, 1 H),7.34-7.26 (m, 5 HRMS(B) ((S)-1- H), 7.22-7.13 (m, 1 H), 5.04 (q, J = 7.1m/z phenylethylamino)pyrimidin- Hz, 1 H), 4.64 (br s, 1 H), 4.34-4.26(m, 2 326.1745 4-yl)oxazolidin-2-one H), 1.85 (br s, 1 H), 1.50 (d, J =7.1 Hz, 3 M⁺ H), 0.70 (br s, 3 H), 0.57 (br s, 3 H) 4:(S)-4-isopropyl-3-(2- 8.10 (d, J = 5.8 Hz, 1 H), 7.35-7.27 (m, 5 HRMS(B)((R)-1- H), 7.23-7.15 (m, 1 H), 4.96 (q, J = 6.9 m/zphenylethylamino)pyrimidin- Hz, 1 H), 4.44 (br s, 1 H), 4.34-4.23 (m, 2326.1746 4-yl)oxazolidin-2-one H), 2.72-2.58 (m, 1 H), 1.51 (d, J = 6.6M⁺ Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.85 (d, J = 7.1 Hz, 3 H) 5:(S)-4-phenyl-3-(2-((S)- 8.07 (d, J = 5.6 Hz, 1 H), 7.38 (d, J = 5.6HRMS(B) 1- Hz, 1 H), 7.28-7.05 (m, 10 H), 5.84 (dd, J = m/zphenylethylamino)pyrimidin- 8.6, 3.5 Hz, 2 H), 4.88 (q, J = 6.8 Hz, 1361.1666 4-yl)oxazolidin-2-one H), 4.83-4.79 (m, 1 H), 4.24 (dd, J =8.6, (M + H)⁺ 3.5 Hz, 1 H), 1.44 (d, J = 6.8 Hz, 3 H) 6:(S)-4-phenyl-3-(2-((R)- 8.08 (d, J = 5.8 Hz, 1 H), 7.43-7.18 (m, HRMS(B)1- 11 H), 5.55 (br s, 1H), 4.74 (t, J = 8.6 Hz, 1 m/zphenylethylamino)pyrimidin- H), 4.63 (br s, 1 H), 4.18 (dd, J = 8.3, 3.8360.1591 4-yl)oxazolidin-2-one Hz, 1 H), 1.19 (d, J = 6.7 Hz, 3 H) M⁺ 7:(S)-3-(2- 8.06 (d, J = 6.1 Hz, 1 H), 7.39-7.28 (m, 6 HRMS(B)(cyclopentylamino)pyrimidin- H), 5.80 (dd, J = 8.8, 3.8 Hz, 1 H), 4.83-m/z 4-yl)-4- 4.80 (m, 1 H), 4.20 (dd, J = 8.6, 4.0 Hz, 1 325.1671phenyloxazolidin-2-one H), 3.79 (br m, 1 H), 1.90-1.99 (m, 1 H), (M +H)⁺ 1.72-1.53 (m, 4 H), 1.49-1.35 (m, 3 H) 8: (S)-3-(2- 8.10 (d, J = 5.6Hz, 1 H), 7.44 (d, J = 5.6 HRMS(B) (cyclopropylamino)pyrimidin- Hz, 1H), 7.36-7.26 (m, 5 H), 5.86 (dd, J = m/z 4-yl)-4- 8.6, 3.5 Hz, 1 H),4.83-4.80 (m, 1 H), 297.1356 phenyloxazolidin-2-one 4.26 (dd, J = 8.6,3.5 Hz, 1 H), 2.40 (br s, 1 (M + H)⁺ H), 0.64-0.71 (m, 1 H), 0.54 (br s,1 H), 0.44-0.37 (m, 1 H), 0.25 (br s, 1 H) 9: (S)-3-(2- 8.06 (d, J = 6.1Hz, 1 H), 7.38-7.27 (m, 6 HRMS(B) (cycloheptylamino)pyrimidin- H), 5.82(dd, J = 8.6, 3.5 Hz, 1 H), 4.83- m/z 4-yl)-4- 4.80 (m, 1 H), 4.21 (dd,J = 8.6, 3.5 Hz, 1 353.1961 phenyloxazolidin-2-one H), 3.57 (br s, 1 H),1.90 (br s, 1 H), 1.69- (M + H)⁺ 1.42 (m, 8 H), 1.32-1.18 (m, 3 H) 10:(R)-4-phenyl-3-(2-((S)- 8.08 (d, J = 5.8 Hz, 1 H), 7.43-7.18 (m, HRMS(B)1- 11 H), 5.54 (br s, 1 H), 4.74 (t, J = 8.6 Hz, m/zphenylethylamino)pyrimidin- 1 H), 4.62 (br s, 1 H), 4.18 (dd, J = 8.8,3.8 361.1712 4-yl)oxazolidin-2-one Hz, 1 H), 1.19 (d, J = 6.6 Hz, 3 H)(M + H)⁺ 11: (R)-4-phenyl-3-(2-((R)- 8.07 (d, J = 5.8 Hz, 1 H), 7.38 (d,J = 5.8 HRMS(B) 1- Hz, 1 H), 7.28-7.05 (m, 10 H), 5.84 (dd, J = m/zphenylethylamino)pyrimidin- 8.3, 3.3 Hz, 1 H), 4.88 (q, J = 6.9 Hz, 1361.1661 4-yl)oxazolidin-2-one H), 4.82-4.78 (m, 1 H), 4.24 (dd, J =8.6, (M + H)⁺ 3.5 Hz, 1 H), 1.44 (d, J = 6.9 Hz, 3 H) 12:(S)-4-isopropyl-3-(2- 8.11 (d, J = 5.6 Hz, 1 H), 7.33-7.26 (m, 5 HRMS(B)((S)-1- H), 7.22-7.15 (m, 1 H), 4.83-4.79 (m, 1 m/zphenylpropylamino)pyrimidin- H), 4.68 (br s, 1 H), 4.36-4.28 (m, 2 H),341.1974 4-yl)oxazolidin-2-one 1.84 (quin, J = 7.3 Hz, 2 H), 0.99 (t, J= 7.3 (M + H)⁺ Hz, 3 H), 0.76 (br s, 3 H), 0.59 (br s, 3 H) 13:(S)-4-isopropyl-3-(2- 8.09 (d, J = 5.8 Hz, 1 H), 7.34-7.27 (m, 5 HRMS(B)((R)-1- H), 7.24-7.16 (m, 1 H), 4.74 (t, J = 6.8 m/zphenylpropylamino)pyrimidin- Hz, 1 H), 4.52 (br s, 1 H), 4.36-4.26 (m, 2341.1976 4-yl)oxazolidin-2-one H), 2.66 (td, J = 6.9, 3.8 Hz, 1 H),1.95- (M + H)⁺ 1.75 (m, 2 H), 1.02 (d, J = 7.1 Hz, 3 H), 0.96 (t, J =7.3 Hz, 3 H), 0.86 (d, J = 7.1 Hz, 3 H) 14: provided (S)-4- 8.09 (d, J =5.8 Hz, 1 H), 7.32-7.23 (m, 3 HRMS(B) benzhydryl-3-(2-((S)-1- H),7.20-7.16 (br m, 6 H), 7.00 (br s, 5 m/z phenylethylamino)pyrimidin- H),6.72 (br s, 2 H), 5.76-5.68 (m, 1 H), 451.2126 4-yl)oxazolidin-2-one5.04 (q, J = 7.1 Hz, 1 H), 4.59 (t, J = 8.8 (M + H)⁺ Hz, 1 H), 4.50 (brs, 1H), 4.47 (dd, J = 9.1, 2.5 1H), 1.44 (d, J = 7.1 Hz, 3 H) 15:(4S,5R)-4-methyl-5- 8.12 (d, J = 5.8 Hz, 1 H), 7.45-7.30 (m, 8 HRMS(B)phenyl-3-(2-((S)-1- H), 7.20 (t, J = 7.6 Hz, 2 H), 7.10-7.07 m/zphenylethylamino)pyrimidin- (m, 1 H), 5.80 (d, J = 7.1 Hz, 1 H), 5.10-375.1823 4-yl)oxazolidin-2-one 4.92 (m, 2 H), 1.49 (d, J = 7.0 Hz, 3 H),(M + H)⁺ 0.37 (br s, 3 H) 16: 3-(2- 8.07 (d, J = 5.7 Hz, 1 H), 7.32 (d,J = 5.8 HRMS(B) (cyclopentylamino)pyrimidin- Hz, 1 H), 4.48 (t, J = 8.1Hz, 2 H), 4.22- m/z 4-yl)oxazolidin-2-one 4.16 (m, 3 H), 2.02 (dq, J =12, 6.1 Hz, 2 248.1275 H), 1.70-1.80 (m, 2 H), 1.67-1.47 (m, 4 M⁺ H) 17:(S)-4-benzyl-3-(2- 8.13 (d, J = 5.8 Hz, 1 H), 7.35-7.21 (m, 6 HRMS(B)(cyclopentylamino)pyrimidin- H), 5.14-5.04 (m, 1 H), 4.36 (t, J = 8.4m/z 4-yl)oxazolidin-2-one Hz, 1 H), 4.33-4.24 (m, 2 H), 3.37-3.33338.1749 (m, 1 H), 3.06 (dd, J = 13, 8.3 Hz, 1 H), M⁺ 2.11-1.98 (m, 2H), 1.86-1.71 (m, 2 H), 1.70-1.53 (m, 4H) 18: (R)-4-benzyl-3-(2- 8.13(d, J = 5.6 Hz, 1 H), 7.35-7.21 (m, 6 HRMS(B)(cyclopentylamino)pyrimidin- H), 5.14-5.05 (m, 1 H), 4.36 (t, J = 8.5m/z 4-yl)oxazolidin-2-one Hz, 1 H), 4.32-4.26 (m, 2 H), 3.37-3.33338.1748 (m, 1 H), 3.06 (dd, J = 13, 8.3 Hz, 1 H), M⁺ 2.13-1.99 (m, 2H), 1.85-1.71 (m, 2 H), 1.70-1.51 (m, 4 H) 19: (4R,5S)-4-methyl-5- 8.11(d, J = 5.8 Hz, 1 H), 7.48-7.28 (m, HRMS(B) phenyl-3-(2-((S)-1- 10 H),7.24-7.21 (m, 1 H), 5.70 (d, J = m/z phenylethylamino)pyrimidin- 6.8 Hz,1 H), 4.96-4.90 (m, 1 H), 4.65 (br 375.1824 4-yl)oxazolidin-2-one s, 1H)1.49 (d, J = 7.1 Hz, 3 H), 0.97 (d, J = (M + H)⁺ 6.6 Hz, 3 H) 20:(S)-4-benzhydryl-3-(2- 8.13 (d, J = 5.8 Hz, 1 H), 7.47-7.40 (m, 2HRMS(B) ((R)-1- H), 7.35-7.22 (m, 5 H), 7.19-7.10 (m, 5 m/zphenylethylamino)pyrimidin- H), 7.01-6.99 (m, 2 H), 6.89 (br s, 2 H),451.2134 4-yl)oxazolidin-2-one 5.26 (br s, 1 H), 5.09 (br s, 1 H), 4.76(br s, (M + H)⁺ 1 H), 4.54-4.44 (m, 2 H), 1.37 (d, J = 7.1 Hz, 3 H) 21:(R)-4-isopropyl-3-(2- 8.10 (d, J = 5.8 Hz, 1 H), 7.35-7.27 (m, 5 HRMS(B)((S)-1- H), 7.20-7.17 (m, 1 H), 4.96 (q, J = 6.7 m/zphenylethylamino)pyrimidin- Hz, 1 H), 4.44 (br s, 1 H), 4.32 (dd, J =9.1, 327.1824 4-yl)oxazolidin-2-one 2.5 Hz, 1 H), 4.25 (t, J = 8.6 Hz, 1H), 2.65 (M + H)⁺ (dtd, J = 14, 7.0, 3.5 Hz, 1 H), 1.51 (d, J = 7.1 Hz,3 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.85 (d, J = 7.1 Hz, 3 H) 22:(R)-4-isopropyl-3-(2- 8.12 (d, J = 5.8 Hz, 1 H), 7.37-7.25 (m, 5 HRMS(B)((R)-1- H), 7.19-7.16 (m, 1H), 5.04 (q, J = 6.9 m/zphenylethylamino)pyrimidin- Hz, 1 H), 4.64 (br s, 1 H), 4.35-4.26 (m, 2327.1821 4-yl)oxazolidin-2-one H), 1.88 (br s, 1 H), 1.50 (d, J = 6.6Hz, 3 (M + H)⁺ H), 0.70 (br s, 3 H), 0.57 (br s, 3 H) 23:(S)-4-isopropyl-5,5- 8.13 (d, J = 5.8 Hz, 1 H), 7.35-7.26 (m, 5 HRMS(B)dimethyl-3-(2-((S)-1- H), 7.19-7.16 (m, 1H), 5.08-5.03 (m, 1 m/zphenylethylamino)pyrimidin- H), 4.45 (br s, 1 H), 1.99 (br s, 1 H), 1.52355.2132 4-yl)oxazolidin-2-one (s, 3 H), 1.50 (d, J = 7.1 Hz, 3 H), 1.41(s, (M + H)⁺ 3 H), 0.73 (br s, 3 H), 0.58 (br s, 3 H) 24:(S)-4-isopropyl-5,5- 8.10 (d, J = 5.8 Hz, 1 H), 7.34-7.25 (m, 5 HRMS(B)dimethyl-3-(2-((R)-1- H), 7.18-7.15 (m, 1 H), 4.93 (br s, 1 H), m/zphenylethylamino)pyrimidin- 4.32 (br s, 1 H), 2.25 (td, J = 6.8, 3.5 Hz,1 355.2128 4-yl)oxazolidin-2-one H), 1.50 (d, J = 7.1 Hz, 3 H), 1.49 (s,3 H), (M + H)⁺ 1.09 (br s, 3 H), 1.03 (d, J = 7.1 Hz, 3 H), 0.95 (d, J =7.1 Hz, 3 H) 25: (4R,5S)-4-methyl-5- 8.12 (d, J = 5.8 Hz, 1 H),7.45-7.30 (m, 8 HRMS(B) phenyl-3-(2-((R)-1- H), 7.20 (t, J = 7.3 Hz, 2H), 7.10-7.06 m/z phenylethylamino)pyrimidin- (m, 1 H), 5.80 (d, J = 7.0Hz, 1 H), 5.01- 375.1823 4-yl)oxazolidin-2-one 4.94 (m, 2 H), 1.49 (d, J7.0 Hz, 3 H), 0.30 (M + H)⁺ (br s, 3H) 26: (4S,5R)-4-methyl-5- 8.10 (d,J = 5.8 Hz, 1 H), 7.48-7.28 (m, HRMS(B) phenyl-3-(2-((R)-1- 10 H),7.24-7.20 (m, 1 H), 5.69 (br s, 1 m/z phenylethylamino)pyrimidin- H),5.01-4.93 (m, 1 H), 4.59 (br s, 1 375.1819 4-yl)oxazolidin-2-one H)1.49(d, J = 7.1 Hz, 3 H), 0.96 (d, J = 6.5 (M + H)⁺ Hz, 3 H) 27:(S)-5,5-dimethyl-4- δ 8.08 (d, J = 5.9 Hz, 1 H), 7.44-7.39 (m, HRMS(B)phenyl-3-(2-((R)-1- 3 H), 7.36-7.29 (m, 5 H), 7.22-7.17 (m, m/zphenylethylamino)pyrimidin- 3 H), 5.16 (br s, 1 H), 4.55 (br s, 1 H),1.49 389.1974 4-yl)oxazolidin-2-one (s, 3 H), 1.18 (d, J = 6.8 Hz, 3 H),0.96 (s, (M + H)⁺ 3 H) 28: (S)-3-(2-((S)-2,3- 8.16 (d, J = 5.8 Hz, 1 H),7.41 (d, J = 5.9 HRMS(B) dihydro-1H-inden-1- Hz, 1 H), 7.25-7.13 (m, 4H), 5.48 (t, J = m/z ylamino)pyrimidin-4-yl)-4- 7.8 Hz, 1 H), 4.79-4.68(m, 1 H), 4.36 (d, 339.1825 isopropyloxazolidin-2-one J = 6.1 Hz, 2 H),3.01 (ddd, J = 16, 8.6, 3.0 (M + H)⁺ Hz, 1 H), 2.94-2.81 (m, 1 H),2.66-2.54 (m, 2 H), 2.01-1.92 (m, 1 H), 0.86 (d, J = 6.9 Hz, 3 H), 0.85(d, J = 6.9 Hz, 3 H) 29: (S)-3-(2-((R)-2,3- 8.15 (d, J = 5.8 Hz, 1 H),7.41 (d, J = 5.8 HRMS(B) dihydro-1H-inden-1- Hz, 1 H), 7.29-7.15 (m, 4H), 5.48 (t, J = m/z ylamino)pyrimidin-4-yl)-4- 7.6 Hz, 1 H), 4.83-4.79(m, 1 H), 4.41- 339.1830 isopropyloxazolidin-2-one 4.36 (m, 2 H), 3.03(ddd, J = 16, 8.8, 3.3 (M + H)⁺ Hz, 1 H), 2.86 (dt, J = 16, 8.0 Hz, 1H), 2.64-2.50 (m, 2 H), 2.00-1.91 (m, 1 H), 0.93 (d, J = 7.1 Hz, 3 H),0.87 (d, J = 7.1 Hz, 3 H) 30: (4R,5S)-4,5-diphenyl- 8.12 (d, J = 5.8 Hz,1 H), 7.48 (d, J = 5.8 HRMS(B) 3-(2-((S)-1- Hz, 1 H), 7.33-7.20 (m, 5H), 7.13-7.08 m/z phenylethylamino)pyrimidin- (m, 6 H), 7.03-7.00 (m, 2H), 6.88-6.86 437.1982 4-yl)oxazolidin-2-one (m, 2 H), 5.99 (d, J = 8.0Hz, 1 H), 5.76 (br (M + H)⁺ s, 1 H), 4.53 (br s, 1 H), 1.11 (br s, 3 H)31: (S)-4-isobutyl-3-(2- 8.11 (d, J = 5.8 Hz, 1 H), 7.36-7.28 (m, 5HRMS(B) ((S)-1- H), 7.21-7.18 (m, 1 H), 5.18 (q, J = 6.9 m/zphenylethylamino)pyrimidin- Hz, 1 H), 4.83-4.79 (m, 1 H), 4.46 (t, J =341.1974 4-yl)oxazolidin-2-one 8.5 Hz, 1 H), 4.23 (dd, J = 9.0, 3.0 Hz,1 (M + H)⁺ H), 1.57 (br s, 2 H), 1.53 (d, J = 7.0 Hz, 3 H), 1.33 (br s,1 H), 0.82 (br s, 3 H), 0.73 (br s, 3 H) 32: (S)-4-isobutyl-3-(2- 8.09(d, J = 5.8 Hz, 1 H), 7.36-7.27 (m, 5 HRMS(B) ((R)-1- H), 7.21-7.18 (m,1 H), 5.16 (q, J = 7.0 m/z phenylethylamino)pyrimidin- Hz, 1 H), 4.69(br s, 1 H), 4.42 (t, J = 8.3 341.1972 4-yl)oxazolidin-2-one Hz, 1 H),4.24 (dd, J = 8.8, 2.8 Hz, 1 H), (M + H)⁺ 1.92-1.86 (m, 1 H), 1.80-1.70(m, 1 H), 1.58 (ddd, J = 13, 10, 4.8 Hz, 1 H), 1.52 (d, J = 7.0 Hz, 3H), 1.07 (d, J = 6.5 Hz, 3 H), 0.98 (d, J = 6.5 Hz, 3 H) 33:(4S)-4-isopropyl-3-(2- 8.49-8.48 (m, 1 H), 8.13 (dd, J = 10, 5.8 HRMS(B)(1-(pyridin-2- Hz, 1 H), 7.75 (td, J = 7.7, 1.8 Hz, 1 H), m/zyl)ethylamino)pyrimidin-4- 7.43-7.36 (m, 2 H), 7.29-7.23 (m, 1 H),328.1762 yl)oxazolidin-2-one 5.08-4.99 (m, 1 H), 4.60 (br s, 0.5 H),(M + H)⁺ 4.34-4.22 (m, 2.5 H), 2.63-2.56 (m, 0.5 H), 1.55 (d, J = 7.0Hz, 1.5 H), 1.54 (d, J = 7.0 Hz, 1.5 H), 1.53 (br s, 0.5 H), 0.97 (d, J= 7.1 Hz, 1.5 H), 0.83 (d, J = 7.1 Hz, 1.5 H), 0.65 (br s, 1.5 H), 0.55(br s, 1.5 H) 34: (4S)-4-isopropyl-3-(2- 8.45-8.43 (m, 2 H), 8.14 (dd, J= 12, 5.6 HRMS(B) (1-(pyridin-4- Hz, 1 H), 7.43-7.37 (m, 2 H), 5.05 (q,J = m/z yl)ethylamino)pyrimidin-4- 7.1 Hz, 0.5 H), 4.99-4.95 (br m, 0.5H), 328.1772 yl)oxazolidin-2-one 4.59 (br s, 0.5 H), 4.33-4.26 (m, 2.5H), (M + H)⁺ 2.64-2.59 (m, 0.5 H), 1.53 (d, J = 7.1 Hz, 3.5 H), 0.97 (d,J = 7.1 Hz, 1.5 H), 0.84 (d, J = 7.1 Hz, 1.5 H), 0.62 (br s, 1.5 H),0.57 (br s, 1.5 H) 35: (S)-4-isopropyl-3-(2- 8.19-8.16 (m, 2 H), 7.88(d, J = 8.1 Hz, 1 HRMS(B) ((S)-1-(naphthalen-1- H), 7.72 (d, J = 8.1 Hz,1 H), 7.56-7.45 m/z yl)ethylamino)pyrimidin-4- (m, 3 H), 7.40-7.32 (m, 2H), 5.80 (q, J = 377.1969 yl)oxazolidin-2-one 6.6 Hz, 1 H), 4.32 (br s,1 H), 4.17-4.13 (M + H)⁺ (m, 1 H), 4.05 (br s, 1 H), 1.64 (d, J = 7.1Hz, 3 H), 1.15 (br s, 1 H), 0.23 (br s, 3 H), −0.31 (br s, 3 H) 36:(S)-4-isopropyl-3-(2- 8.09 (d, J = 5.6 Hz, 1 H), 7.33 (d, J = 6.1HRMS(B) ((R)-1-(4- Hz, 1 H), 7.28-7.24 (m, 2 H), 6.87-6.83 m/zmethoxyphenyl)ethylami- (m, 2 H), 4.93 (q, J = 6.9 Hz, 1 H), 4.52 (br357.1928 no)pyrimidin-4- s, 1 H), 4.35-4.26 (m, 2 H), 3.75 (s, 3 H),(M + H)⁺ yl)oxazolidin-2-one 2.65 (ddt, J = 10, 6.9, 3.5, 1 H), 1.48 (d,J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.83 (d, J = 6.8 Hz, 3 H)37: (4S,5R)-4,5-diphenyl- 8.10 (d, J = 5.8 Hz, 1 H), 7.50 (d, J = 5.8HRMS(B) 3-(2-((S)-1- Hz, 1 H), 7.12-7.09 (m, 6 H), 7.06-7.03 m/zphenylethylamino)pyrimidin- (m, 2 H), 7.01-6.97 (m, 5 H), 6.83-6.81437.1984 4-yl)oxazolidin-2-one (m, 2 H), 6.10 (s, 2 H), 4.86-4.81 (br m,1 (M + H)⁺ H), 1.42 (d, J = 6.5 Hz, 3 H) 38: (4S,5R)-4,5-diphenyl-8.11-8.09 (m, 1 H), 7.47 (d, J = 5.8 Hz, 1 HRMS(B) 3-(2-((R)-1- H),7.32-7.20 (m, 5 H), 7.12-7.07 (m, 6 m/z phenylethylamino)pyrimidin- H),7.02-6.99 (m, 2 H), 6.86 (d, J = 6.5 437.1970 4-yl)oxazolidin-2-one Hz,2 H), 5.98-5.93 (br m, 1 H), 5.75 (br (M + H)⁺ s, 1 H), 4.53 (br s, 1H), 1.11 (br s, 3 H) 39: (4R,5S)-4,5-diphenyl- 8.09 (d, J = 5.9 Hz, 1H), 7.50 (d, J = 5.8 HRMS(B) 3-(2-((R)-1- Hz, 1 H), 7.11-7.09 (m, 6 H),7.05-7.03 m/z phenylethylamino)pyrimidin- (m, 2 H), 7.00-6.95 (m, 5 H),6.82-6.80 437.1975 4-yl)oxazolidin-2-one (m, 2 H), 6.09 (s, 2 H),4.87-4.81 (br m, 1 (M + H)⁺ H), 1.41 (d, J = 7.0 Hz, 3 H) 40:(S)-4-isopropyl-3-(2- 8.16 (d, J = 8.4 Hz, 1 H), 8.12 (d, J = 5.8HRMS(B) ((R)-1-(naphthalen-1- Hz, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.56-m/z yl)ethylamino)pyrimidin-4- 7.45 (m, 3 H), 7.42-7.38 (m, 1 H), 7.33377.1981 yl)oxazolidin-2-one (d, J = 5.8 Hz, 1 H), 5.81 (q, J = 6.6 Hz,1 (M + H)⁺ H), 4.15 (br s, 1 H), 4.03 (br s, 1 H), 2.56 (td, J = 7.1,3.5 Hz, 1 H), 1.65 (d, J = 7.1 Hz, 3 H), 0.78 (d, J = 6.6 Hz, 3 H), 0.74(br s, 3 H) 41: (S)-4-isopropyl-3-(2- 8.11 (d, J = 5.8 Hz, 1 H), 7.33(d, J = 5.9 HRMS(B) ((S)-1-(4- Hz, 1 H), 7.22 (d, J = 8.6 Hz, 2 H),6.85- m/z methoxyphenyl)ethylami- 6.82 (m, 2 H), 4.98 (q, J = 6.9 Hz, 1H), 357.1922 no)pyrimidin-4- 4.67-4.63 (m, 1 H), 4.34-4.27 (m, 2 H),(M + H)⁺ yl)oxazolidin-2-one 3.75 (s, 3 H), 1.94 (br s, 1 H), 1.48 (d, J= 7.1 Hz, 3 H), 0.73 (br s, 3 H), 0.61 (br s, 3 H) 42:(S)-4-isopropyl-3-(2- 9.11 (s, 1 H), 9.03 (s, 2 H), 8.14 (d, J = 5.8HRMS(B) ((S)-1-(4-(pyrimidin-5- Hz, 1 H), 7.69-7.66 (m, 2 H), 7.52 (d, J= m/z yl)phenyl)ethylamino)pyrimidin- 8.1 Hz, 2 H), 7.35 (d, J = 5.8 Hz,1 H), 5.11 405.2035 4-yl)oxazolidin-2- (q, J = 6.9 Hz, 1 H), 4.65 (br s,1 H), 4.35- (M + H)⁺ one 4.26 (m, 2 H), 1.80 (br s, 1 H), 1.55 (d, J =7.1 Hz, 3 H), 0.66 (br s, 3 H), 0.55 (br s, 3 H) 43:(S)-4-isopropyl-3-(2- 8.10 (d, J = 5.9 Hz, 1 H), 7.80-7.75 (m, 4 HRMS(B)((R)-1-(naphthalen-2- H), 7.51-7.48 (m, 1 H), 7.43-7.36 (m, 2 m/zyl)ethylamino)pyrimidin-4- H), 7.32 (d, J = 5.8 Hz, 1 H), 5.15-5.07377.1984 yl)oxazolidin-2-one (m, 1 H), 4.36 (br s, 1 H), 4.24 (dd, J =9.1, (M + H)⁺ 2.5 Hz, 1 H), 4.14-4.06 (br m, 1 H), 2.67 (dtd, J = 14,6.9, 3.5 Hz, 1 H), 1.60 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3 H),0.83 (d, J = 7.1 Hz, 3 H) 44: (R)-3-(2-((S)-1-(4- 8.09-8.07 (m, 1 H),7.41-7.18 (m, 8 H), HRMS(B) fluorophenyl)ethylami- 7.12-7.07 (m, 2 H),5.21 (s, 1 H), 4.99- m/z no)pyrimidin-4-yl)-5,5- 4.93 (m, 1 H), 1.50 (s,3 H), 1.24 (d, J = 407.188 dimethyl-4- 7.1 Hz, 3 H), 0.98 (s, 3 H) (M +H)⁺ phenyloxazolidin-2-one 45: (R)-4-isobutyl-3-(2- 8.10 (d, J = 5.8 Hz,1 H), 7.36-7.27 (m, 5 HRMS(B) ((R)-1- H), 7.22-7.17 (m, 1 H), 5.18 (q, J= 6.9 m/z phenylethylamino)pyrimidin- Hz, 1 H), 4.82-4.78 (m, 1 H), 4.46(t, J = 341.1967 4-yl)oxazolidin-2-one 8.6 Hz, 1 H), 4.22 (dd, J = 8.6,3.0 Hz, 1 (M + H)⁺ H), 1.62-1.54 (m, 2 H), 1.53 (d, J = 7.0 Hz, 3 H),1.36-1.30 (m, 1 H), 0.82 (br s, 3 H), 0.73 (br s, 3 H) 46:(4S,5R)-5-methyl-4- 8.05 (d, J = 5.8 Hz, 1 H), 7.42 (d, J = 5.8 HRMS(B)phenyl-3-(2-((S)-1- Hz, 1 H), 7.31-7.26 (m, 3 H), 7.19-7.11 m/zphenylethylamino)pyrimidin- (m, 5 H), 7.02 (br s, 2 H), 5.80 (d, J = 7.5375.1828 4-yl)oxazolidin-2-one Hz, 1 H), 5.11-5.04 (m, 1 H), 4.85 (q, J= (M + H)⁺ 6.7 Hz, 1 H), 1.44 (d, J = 7.0 Hz, 3 H), 0.97 (d, J = 6.5 Hz,3 H) 47: (4S,5R)-5-methyl-4- 8.06 (d, J = 5.8 Hz, 1 H), 7.43-7.40 (m, 3HRMS(B) phenyl-3-(2-((R)-1- H), 7.37-7.30 (m, 5 H), 7.23-7.17 (m, 3 m/zphenylethylamino)pyrimidin- H), 5.51 (br d, J = 7.1 Hz, 1 H), 4.99(quin, 375.1819 4-yl)oxazolidin-2-one J = 6.8 Hz, 1 H), 4.63 (br s, 1H), 1.16 (br (M + H)⁺ d, J = 6.3 Hz, 3 H), 0.95 (d, J = 6.5 Hz, 3 H) 48:(S)-4-benzyl-5,5- (CDCl₃) 8.18 (d, J = 5.7 Hz, 1 H), 7.43 (d, J =HRMS(B) dimethyl-3-(2-((S)-1- 5.7 Hz, 1 H), 7.31-7.17 (m, 10 H), 5.34m/z phenylethylamino)pyrimidin- (br s, 1 H), 5.14 (quin, J = 7.0 Hz, 1H), 403.2133 4-yl)oxazolidin-2-one 4.85 (dd, J = 10, 3.5 Hz, 1 H), 3.22(br d, J = (M + H)⁺ 14 Hz, 1 H), 2.72 (br s, 1 H), 1.57 (d, J = 6.5 Hz,3 H), 1.42 (s, 3 H), 1.33 (s, 3 H) 49: (R)-4-isobutyl-3-(2- 8.09 (d, J =6.1 Hz, 1 H), 7.36-7.27 (m, 5 HRMS(B) ((S)-1- H), 7.21-7.17 (m, 1 H),5.16 (q, J = 7.1 m/z phenylethylamino)pyrimidin- Hz, 1 H), 4.69 (t, J =8.6 Hz, 1 H), 4.41 (t, J = 341.1973 4-yl)oxazolidin-2-one 8.3 Hz, 1 H),4.23 (dd, J = 8.6, 3.0 Hz, 1 (M + H)⁺ H), 1.92-1.86 (m, 1 H), 1.79-1.69(m, 1 H), 1.57 (ddd, J = 13, 10, 4.8 Hz, 1 H), 1.52 (d, J = 7.1 Hz, 3H), 1.07 (d, J = 6.6 Hz, 3 H), 0.98 (d, J = 6.6 Hz, 3 H) 50:(S)-4-isopropyl-3-(2- 8.15 (d, J = 5.7 Hz, 1 H), 7.81-7.73 (m, 4 HRMS(B)((S)-1-(naphthalen-2- H), 7.49-7.38 (m, 3 H), 7.33 (d, J = 5.8 m/zyl)ethylamino)pyrimidin-4- Hz, 1 H), 5.18 (q, J = 7.1 Hz, 1 H), 4.57 (br377.1979 yl)oxazolidin-2-one s, 1 H), 4.30-4.25 (m, 1 H), 4.20 (br s, 1(M + H)⁺ H), 1.60 (d, J = 7.1 Hz, 3 H), 1.59 (br s, 1 H), 0.34 (br s, 6H) 51: (S)-4-isopropyl-3-(2- 8.08 (d, J = 5.6 Hz, 1 H), 7.32 (d, J = 5.6HRMS(B) ((R)-1-p- Hz, 1 H), 7.22 (d, J = 8.1 Hz, 2 H), 7.10 (d, m/ztolylethylamino)pyrimidin- J = 8.1 Hz, 2 H), 4.95-4.90 (m, 1 H), 4.48341.1972 4-yl)oxazolidin-2-one (br s, 1 H), 4.32 (dd, J 9.1, 3.0 Hz, 1H), (M + H)⁺ 4.25 (t, J = 8.8 Hz, 1 H), 2.65 (dtd, J = 14, 7.1, 3.5 Hz,1 H), 2.28 (s, 3 H), 1.48 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3H), 0.84 (d, J = 7.1 Hz, 3 H) 52: (S)-4-benzyl-5,5- (CDCl₃) 8.17 (d, J =5.7 Hz, 1 H), 7.44 (d, J = HRMS(B) dimethyl-3-(2-((R)-1- 5.7 Hz, 1 H),7.38-7.21 (m, 10 H), 5.32 m/z phenylethylamino)pyrimidin- (br s, 1 H),5.02 (br s, 1 H), 4.69-4.68 (br 403.2133 4-yl)oxazolidin-2-one m, 1 H),3.34 (dd, J = 15, 4.0 Hz, 1 H), (M + H)⁺ 2.93 (dd, J = 15, 9.5 Hz, 1 H),1.51 (d, J = 6.9 Hz, 3 H), 1.35 (s, 3 H), 1.29 (s, 3 H) 53:(S)-3-(2-((S)-1- (CDCl₃) 8.56-8.53 (br m, 2 H), 8.18 (d, J = HRMS(B)phenylethylamino)pyrimidin- 5.7 Hz, 1 H), 7.48 (d, J = 5.7 Hz, 1 H), m/z4-yl)-4-(pyridin-3- 7.45-7.34 (m, 1 H), 7.30-7.16 (m, 6 H), 362.1620yl)oxazolidin-2-one 5.77 (dd, J = 8.8, 3.8 Hz, 1 H), 5.26 (br s, 1 (M +H)⁺ H), 4.83 (br s, 1 H), 4.81 (t, J = 8.8 Hz, 1 H), 4.31 (dd, J = 8.8,3.8 Hz, 1 H), 1.51 (d, J = 6.8 Hz, 3 H) 54: 4-(4-methoxyphenyl)- (CDCl₃)8.06 (d, J = 5.7 Hz, 1 H), 7.55- HRMS(B) 5,5-dimethyl-3-(2-((S)-1- 7.52(m, 1 H), 7.37-7.20 (m, 4 H), 7.13- m/z phenylethylamino)pyrimidin- 6.99(m, 3 H), 6.91 (d, J = 8.0 Hz, 1 H), 419.2093 4-yl)oxazolidin-2-one 6.78(d, J = 8.0 Hz, 1 H), 5.87 (br s, 0.5 H), (M + H)⁺ 5.67 (br s, 0.5 H),5.01 (br s, 0.5 H), 4.82 (br s, 0.5 H), 4.64 (br s, 0.5 H), 3.83 (s, 1.5H), 3.78 (s, 1.5 H), 3.36 (br s, 0.5 H), 1.66 (s, 1.5 H), 1.51 (d, J =6.9 Hz, 1.5 H), 1.49 (s, 1.5 H), 1.29-1.27 (m, 1.5 H), 1.04 (s, 1.5 H),1.00 (s, 1.5 H) 55: (R)-3-(2- 8.08 (d, J = 5.8 Hz, 1 H), 7.41 (d, J =5.8 HRMS(B) (benzylamino)pyrimidin-4- Hz, 1 H), 7.30-7.17 (m, 8 H), 7.09(br d, J = m/z yl)-4-phenyloxazolidin-2- 7.1 Hz, 2 H), 5.69 (br dd, J =8.1, 3.0 Hz, 347.1512 one 1 H), 4.76 (t, J = 8.8 Hz, 1 H), 4.28 (dd, J =(M + H)⁺ 44, 15 Hz, 2 H), 4.19 (dd, J = 8.8, 3.8 Hz, 1 H) 56: (S)-3-(2-8.10 (d, J = 5.7 Hz, 1 H), 7.42 (d, J = 5.9 HRMS(B)(benzylamino)pyrimidin-4- Hz, 1 H), 7.31-7.16 (m, 8 H), 7.09 (br d, J =m/z yl)-4-phenyloxazolidin-2- 7.1 Hz, 2 H), 5.71 (br m, 1 H), 4.78 (t, J= 347.1499 one 8.8 Hz, 1 H), 4.28 (dd, J = 45, 15 Hz, 2 H), (M + H)⁺4.21 (dd, J = 8.6, 3.5 Hz, 1 H) 57: (S)-3-(2- 8.13 (d, J = 5.8 Hz, 1 H),7.37 (d, J = 5.8 HRMS(B) (benzylamino)pyrimidin-4- Hz, 1 H), 7.28 (d, J= 4.6 Hz, 4 H), 7.20 m/z yl)-4-isopropyloxazolidin- (dq, J = 8.5, 4.2Hz, 1 H), 4.64 (br s, 1 H), 312.1584 2-one 4.56 (dd, J = 51, 16 Hz, 2H), 4.35-4.29 M⁺ (m, 2 H), 2.31 (br s, 1 H), 0.77 (br s, 3 H), 0.72 (brd, J = 6.6 Hz, 3 H) 58: (4S)-4-isopropyl-3-(2- 8.23 (d, J = 5.8 Hz, 1H), 7.40 (d, J = 5.8 HRMS(B) (1-(4-(4-methylpiperazin- Hz, 1 H),7.28-7.24 (m, 2 H), 7.01-6.98 m/z 1- (m, 2 H), 4.85-4.82 (m, 1 H),4.44-4.39 425.2651 yl)phenyl)ethylamino)pyrimidin- (m, 2 H), 4.03-3.98(m, 1 H), 3.93-3.90 (M + H)⁺ 4-yl)oxazolidin-2- (m, 4 H), 3.30 (s, 3 H),3.21-3.18 (m, 4 one H), 2.60 (dtt, J = 10, 6.9, 3.5 Hz, 1 H), 1.37 (d, J= 7.1 Hz, 3 H), 1.00 (d, J = 7.1 Hz, 3 H), 0.87 (d, J = 6.9 Hz, 3 H) 59:(S)-3-(2-((S)-1-(3,5- 8.17 (br d, J = 5.0 Hz, 1 H), 7.93 (s, 2 H),HRMS(B) bis(trifluoromethyl)phenyl) 7.82 (s, 1 H), 7.40 (d, J = 5.9 Hz,1 H), m/z ethylamino)pyrimidin-4-yl)- 5.21 (q, J = 7.1 Hz, 1 H), 4.59(br s, 1 H), 463.1564 4-isopropyloxazolidin-2- 4.33-4.25 (m, 2 H), 1.69(br s, 1 H), 1.57 (M + H)⁺ one (d, J = 7.1 Hz, 3 H), 0.57 (br s, 6 H)60: (S)-4-isopropyl-3-(2- 8.14 (d, J = 5.8 Hz, 1 H), 7.71 (d, J = 8.6HRMS(B) ((S)-1-(6- Hz, 1 H), 7.67-7.64 (m, 2 H), 7.42 (dd, J = m/zmethoxynaphthalen-2- 8.3, 1.8 Hz, 1 H), 7.33 (d, J = 5.8 Hz, 1 407.2084yl)ethylamino)pyrimidin-4- H), 7.19 (d, J = 2.5 Hz, 1 H), 7.08 (dd, J =(M + H)⁺ yl)oxazolidin-2-one 9.1, 2.5 Hz, 1 H), 5.15 (q, J = 7.1 Hz, 1H), 4.59 (br s, 1 H), 4.29 (t, J = 8.8 Hz, 1 H), 4.24-4.19 (br m, 1 H),3.88 (s, 3 H), 1.74 (br s, 1 H), 1.58 (d, J = 7.1 Hz, 3 H), 0.39 (br s,6 H) 61: (S)-4-isopropyl-3-(2- 8.09 (d, J = 5.8 Hz, 1 H), 7.33 (d, J =5.9 HRMS(B) ((R)-1-(3- Hz, 1 H), 7.20 (t, J = 7.8 Hz, 1 H), 6.92- m/zmethoxyphenyl)ethylami- 6.90 (m, 2 H), 6.75 (ddd, J = 8.1, 2.5, 1.0357.1927 no)pyrimidin-4- Hz, 1 H), 4.94-4.89 (m, 1 H), 4.46 (br s, 1(M + H)⁺ yl)oxazolidin-2-one H), 4.34-4.23 (m, 2 H), 3.75 (s, 3 H), 2.65(dtd, J = 14, 6.9, 3.5 Hz, 1 H), 1.49 (d, J = 7.1 Hz, 3 H), 0.99 (d, J =7.1 Hz, 3 H), 0.85 (d, J = 6.9 Hz, 3 H) 62: (S)-3-(2-((S)-1-(3- 8.14 (d,J 5.8 Hz, 1 H), 7.48 (s, 1 H), 7.37- HRMS(B) bromophenyl)ethylamino)7.28 (m, 3 H), 7.20 (t, J = 7.1 Hz, 1 H), m/z pyrimidin-4-yl)-4- 5.01(q, J = 7.1 Hz, 1 H), 4.62 (br s, 1 H), 405.0937isopropyloxazolidin-2-one 4.34-4.26 (m, 2 H), 1.83 (br s, 1 H), 1.50(M + H)⁺ (d, J = 7.1 Hz, 3 H), 0.71 (br s, 3 H), 0.59 (br s, 3 H) 63:(S)-3-(2-((S)-1-(4- 8.13 (d, J 5.8 Hz, 1 H), 7.44-7.41 (m, 2 HRMS(B)bromophenyl)ethylamino) H), 7.35 (d, J = 5.8 Hz, 1 H), 7.26-7.22 m/zpyrimidin-4-yl)-4- (m, 2 H), 4.98 (q, J = 7.1 Hz, 1 H), 4.60 (br405.0912 isopropyloxazolidin-2-one s, 1 H), 4.33-4.26 (m, 2 H), 1.73 (brs, 1 (M + H)⁺ H), 1.49 (d, J = 7.1 Hz, 3 H), 0.68 (br s, 3 H), 0.58 (brs, 3 H) 64: (S)-3-(2-(1- 8.23 (d, J = 8.1 Hz, 1 H), 8.07 (d, J = 5.8HRMS(B) (naphthalen-1- Hz, 1 H), 7.88-7.86 (m, 1 H), 7.73 (d, J = m/zyl)ethylamino)pyrimidin-4- 8.1 Hz, 1 H), 7.58 (d, J = 7.1 Hz, 1 H),7.54- 335.1500 yl)oxazolidin-2-one 7.45 (m, 2 H), 7.42-7.39 (m, 1 H),7.29 (M + H)⁺ (d, J = 5.8 Hz, 1 H), 5.90 (q, J = 6.7 Hz, 1 H), 4.32 (brs, 1 H), 4.22 (br s, 1 H), 3.98 (br s, 1 H), 3.37 (br s, 1 H), 1.65 (d,J = 6.9 Hz, 3 H) 65: (S)-3-(2-((S)-1- 8.11 (d, J = 5.8 Hz, 1 H),7.80-7.77 (m, 1 HRMS(B) (naphthalen-2- H), 7.73-7.68 (m, 2 H), 7.56 (s,1 H), 7.45- m/z yl)ethylamino)pyrimidin-4- 7.40 (m, 2 H), 7.37 (d, J =5.8 Hz, 1 H), 411.1820 yl)-4-phenyloxazolidin-2- 7.23 (dd, J = 8.6, 1.5Hz, 1 H), 7.08-7.00 (M + H)⁺ one (m, 5 H), 5.80 (dd, J = 8.8, 3.8 Hz, 1H), 5.07 (q, J = 6.9 Hz, 1 H), 4.79 (t, J = 8.7 Hz, 1 H), 4.20 (dd, J =8.6, 3.5 Hz, 1 H), 1.55 (d, J = 6.9 Hz, 3 H) 66: (R)-3-(2-((S)-1- 8.10(d, J = 5.8 Hz, 1 H), 7.82-7.78 (m, 3 HRMS(B) (naphthalen-2- H), 7.69(s, 1 H), 7.47-7.40 (m, 5 H), 7.38- m/z yl)ethylamino)pyrimidin-4- 7.29(m, 4 H), 5.53 (dd, J = 8.8, 3.8 Hz, 1 411.1821yl)-4-phenyloxazolidin-2- H), 4.82 (q, J = 6.9 Hz, 1 H), 4.68 (t, J =(M + H)⁺ one 8.6 Hz, 1 H), 4.15 (dd, J = 8.6, 4.0 Hz, 1 H), 1.31 (d, J =6.9 Hz, 3 H) 67: (S)-3-(2-((R)-1-(3- 8.10 (d, J 5.8 Hz, 1 H), 7.53-7.50(m, 1 HRMS(B) bromophenyl)ethylamino) H), 7.36-7.31 (m, 3 H), 7.21 (t, J= 7.8 m/z pyrimidin-4-yl)-4- Hz, 1 H), 4.94-4.86 (m, 1 H), 4.42 (br s, 1405.0930 isopropyloxazolidin-2-one H), 4.33 (dd, J = 9.1, 2.5, 1 H),4.26 (t, J = (M + H)⁺ 8.8 Hz, 1 H), 2.65 (dtd, J = 14, 7.0, 3.8 Hz, 1H), 1.50 (d, J = 7.1 Hz, 3 H), 1.00 (d, J = 7.1 Hz, 3 H), 0.85 (d, J =7.1 Hz, 3 H) 68: (S)-3-(2-((R)-1-(4- 8.10 (d, J 5.8 Hz, 1 H), 7.45-7.42(m, 2 HRMS(B) bromophenyl)ethylamino) H), 7.35 (d, J = 5.9 Hz, 1 H),7.29-7.25 m/z pyrimidin-4-yl)-4- (m, 2 H), 4.95-4.90 (m, 1 H), 4.44 (brs, 1 405.0934 isopropyloxazolidin-2-one H), 4.34-4.25 (m, 2 H), 2.63(dtd, J = 14, (M + H)⁺ 6.9, 3.5 Hz, 1 H), 1.49 (d, J = 7.1 Hz, 3 H),0.98 (d, J = 7.1 Hz, 3 H), 0.84 (d, J = 7.1 Hz, 3 H) 69:(S)-4-isopropyl-3-(2- 8.12 (d, J = 5.8 Hz, 1 H), 7.34 (d, J = 6.0HRMS(B) ((S)-1-(3- Hz, 1 H), 7.20-7.16 (m, 1 H), 6.89-6.87 m/zmethoxyphenyl)ethylami- (m, 2 H), 6.75-6.73 (m, 1 H), 4.99 (q, J =357.1918 no)pyrimidin-4- 6.7 Hz, 1 H), 4.63 (br s, 1 H), 4.34-4.25 (M +H)⁺ yl)oxazolidin-2-one (m, 2 H), 3.74 (s, 3 H), 1.84 (br s, 1 H), 1.49(d, J = 7.1 Hz, 3 H), 0.68 (br s, 3 H), 0.57 (br s, 3 H) 70:(S)-4-isopropyl-3-(2- 8.11 (d, J = 5.8 Hz, 1 H), 7.33 (d, J = 5.9HRMS(B) ((S)-1-p- Hz, 1 H), 7.18 (d, J = 8.1 Hz, 2 H), 7.08 (d, m/ztolylethylamino)pyrimidin- J = 8.1 Hz, 2 H), 4.99 (q, J = 7.1 Hz, 1 H),341.1977 4-yl)oxazolidin-2-one 4.63 (br s, 1 H), 4.34-4.26 (m, 2 H),2.28 (M + H)⁺ (s, 3 H), 1.86 (br s, 1 H), 1.48 (d, J = 7.1 Hz, 3 H),0.69 (br s, 3 H), 0.58 (br s, 3 H) 71: (S)-4-tert-butyl-3-(2- 8.14 (d, J= 5.7 Hz, 1 H), 7.37-7.34 (m, 2 HRMS(B) ((S)-1- H), 7.30-7.26 (m, 2 H),7.19-7.15 (m, 2 m/z phenylethylamino)pyrimidin- H), 5.00 (q, J = 6.9 Hz,1 H), 4.76 (br s, 1 341.1979 4-yl)oxazolidin-2-one H), 4.41-4.33 (m, 2H), 1.48 (d, J = 7.1 (M + H)⁺ Hz. 3 H), 0.55 (br s, 9 H) 72:(S)-4-tert-butyl-3-(2- 8.09 (d, J = 5.7 Hz, 1 H), 7.35-7.32 (m, 2HRMS(B) ((R)-1- H), 7.29-7.24 (m, 3 H), 7.19-7.15 (m, 1 m/zphenylethylamino)pyrimidin- H), 5.01-4.96 (m, 1 H), 4.68 (br s, 1 H),341.1974 4-yl)oxazolidin-2-one 4.39 (d, H = 9.2 Hz, 1 H), 4.15 (br s, 1H), (M + H)⁺ 1.50 (d, J = 7.0 Hz. 3 H), 0.94 (s, 9 H) 73:(R)-3-(2-((S)-1-(3- 8.09 (d, J = 5.8 Hz, 1 H), 7.42-7.37 (m, 3 HRMS(B)methoxyphenyl)ethylami- H), 7.34-7.28 (m, 3 H), 7.21 (t, J = 7.8 m/zno)pyrimidin-4-yl)-4- Hz, 1 H), 6.86-6.83 (m, 2 H), 6.78-6.76 391.1768phenyloxazolidin-2-one (m, 1 H), 5.58 (dd, J = 8.6, 4.0 Hz, 1 H), (M +H)⁺ 4.74 (t, J = 8.7 Hz, 1 H), 4.66-4.61 (m, 1 H), 4.18 (dd, J = 8.6,4.0 Hz, 1 H), 3.77 (s, 3 H), 1.20 (d, J = 6.9 Hz, 3 H) 74:(S)-3-(2-((S)-1- 8.55 (d, J = 4.5 Hz, 1 H), 8.10 (d, J = 6.0 HRMS(B)phenylethylamino)pyrimidin- Hz, 1 H), 7.64 (d, J = 6.0 Hz, 1 H), 7.43(br m/z 4-yl)-4-(pyridin-2- s, 1 H), 7.26-7.15 (m, 4 H), 7.06 (br s, 2362.1624 yl)oxazolidin-2-one H), 6.92 (br s, 1 H), 5.84 (dd, J = 8.7,3.2 (M + H)⁺ Hz, 1 H), 4.94 (br s, 1 H), 4.88-4.78 (m, 2 H), 4.48 (dd, J= 8.7, 3.2 Hz, 1 H), 1.51 (d, J = 6.9 Hz, 3 H) 75: (S)-3-(2-((S)-1- 8.43(br s, 2 H), 8.16 (br d, J = 5.0 Hz, 1 HRMS(B)phenylethylamino)pyrimidin- H), 7.65 (br s, 1 H), 7.36-7.09 (br m, 6 m/z4-yl)-4-(pyridin-4- H), 6.90 (br s, 1 H), 5.88 (br s, 1 H), 4.83362.1623 yl)oxazolidin-2-one (t, J = 8.8 Hz, 1 H), 4.78 (br s, 1 H),4.23 (M + H)⁺ (br s, 1 H), 1.34 (d, J = 7.0 Hz, 3 H) 76:(S)-4-isopropyl-3-(2- 8.11 (d, J = 5.8 Hz, 1 H), 7.66 (s, 1 H), HRMS(B)((R)-1-(3- 7.64-7.61 (m, 1 H), 7.53-7.49 (m, 2 H), m/z(trifluoromethyl)phenyl)eth- 7.36 (d, J = 5.9 Hz, 1 H), 5.05-4.99 (m, 1395.1686 ylamino)pyrimidin-4- H), 4.42 (br s, 1 H), 4.33 (dd, J = 9.1,3.0 (M + H)⁺ yl)oxazolidin-2-one Hz, 1 H), 4.24 (t, J = 8.6 Hz, 1 H),2.68- 2.60 (m, 1 H), 1.54 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3H), 0.85 (d, J = 7.0 Hz, 3 H) 77: (S)-4-isopropyl-3-(2- 8.11 (d, J = 5.8Hz, 1 H), 7.60 (d, J = 8.3 HRMS(B) ((R)-1-(4- Hz, 2 H), 7.54 (d, J = 8.3Hz, 2 H), 7.36 (d, m/z (trifluoromethyl)phenyl)eth- J = 5.8 Hz, 1 H),5.07-5.00 (m, 1 H), 4.39 395.1698 ylamino)pyrimidin-4- (br s, 1 H),4.33-4.30 (m, 1 H), 4.27- (M + H)⁺ yl)oxazolidin-2-one 4.23 (m, 1 H),2.63 (dtd, J = 14, 7.1, 3.5 Hz, 1 H), 1.54 (d, J = 7.0 Hz, 3 H), 0.98(d, J = 7.1 Hz, 3 H), 0.84 (d, J = 7.1 Hz, 3 H) 78: (S)-3-(2-((R)-1-(2-8.10 (d, J = 5.8 Hz, 1 H), 7.40-7.34 (m, 2 HRMS(B)fluorophenyl)ethylami- H), 7.24-7.18 (m, 1 H), 7.10-7.02 (m, 2 m/zno)pyrimidin-4-yl)-4- H), 5.28 (q, J = 7.1 Hz, 1 H), 4.42 (br s, 1345.1727 isopropyloxazolidin-2-one H), 4.32 (dd, J = 9.1, 2.5 Hz, 1 H),4.24 (t, (M + H)⁺ J = 8.8 Hz, 1 H), 2.64 (dtd, J = 14, 7.0, 3.8 Hz, 1H), 1.50 (d, J = 7.1 Hz, 3 H), 0.98 (d, J = 7.1 Hz, 3 H), 0.84 (d, J =7.1 Hz, 3 H) 79: (S)-4-methyl-4-phenyl- 8.15 (d, J = 5.8 Hz, 1 H),7.44-7.38 (m, 3 HRMS(B) 3-(2-((S)-1- H), 7.36-7.21 (m, 6 H), 7.15-7.13(m, 2 m/z phenylethylamino)pyrimidin- H), 5.40 (br s, 1 H), 4.22-4.17(m, 2 H), 375.1809 4-yl)oxazolidin-2-one 4.15 (br s, 1 H), 1.63 (br s, 3H), 1.15 (d, J (M + H)⁺ 6.6 Hz, 3 H) 80: (S)-4-isopropyl-3-(2- 8.11 (d,J = 5.8 Hz, 1 H), 7.33 (d, J = 5.8 HRMS(B) ((S)-1-(4- Hz, 1 H),7.22-7.19 (m, 2 H), 6.92-6.89 m/z morpholinophenyl)ethylami- (m, 2 H),5.00-4.95 (m, 1 H), 4.66 (br s, 1 412.2359 no)pyrimidin-4- H), 4.58 (brs, 1 H), 4.35-4.27 (m, 2 H), (M + H)⁺ yl)oxazolidin-2-one 3.82-3.80 (m,4 H), 3.09-3.07 (m, 4 H), 1.48 (d, J = 7.1 Hz, 3 H), 0.73 (br s, 3 H),0.60 (br s, 3 H) 81: (4R)-4-methyl-4- HRMS(B) phenyl-3-(2-((1-(1-phenyl-m/z 1H-pyrazol-4- 441.2049 yl)ethyl)amino)pyrimidin-4- (M + H)⁺yl)oxazolidin-2-one 82: (S)-3-(2-((S)-1-(4- 8.16 (d, J = 5.8 Hz, 1 H),7.36 (d, J = 5.8 HRMS(B) bromo-3,5- Hz, 1 H), 6.64 (s, 2 H), 5.00-4.95(m, 1 m/z dimethoxyphenyl)ethylami- H), 4.58 (br s, 1 H), 4.33-4.23 (m,2 H), 465.1134 no)pyrimidin-4-yl)-4- 3.79 (s, 6 H), 1.54 (d, J = 7.0 Hz,3 H), (M + H)⁺ isopropyloxazolidin-2-one 0.55 (br s, 6 H) 83:(4S)-3-(2-(1-(1H-indol- 8.11 (d, J = 5.8 Hz, 0.5 H), 8.09 (d, J = 5.8HRMS(B) 5-yl)ethylamino)pyrimidin- Hz, 0.5 H), 7.52 (s, 0.5 H), 7.46 (s,0.5 H), m/z 4-yl)-4- 7.32-7.29 (m, 2 H), 7.19-7.18 (m, 1 H), 366.1928isopropyloxazolidin-2-one 7.10 (ddd, J = 14, 8.6, 1.5 Hz, 1 H), 6.36(M + H)⁺ (dt, J = 4.0, 3.0 Hz, 1 H), 5.11 (q, J = 6.9 Hz, 0.5 H), 5.05(q, J = 6.8 Hz, 0.5 H), 4.64 (br s, 0.5 H), 4.50 (br s, 0.5 H),4.33-4.19 (m, 2 H), 2.74-2.64 (m, 0.5 H), 1.86 (br s, 0.5 H), 1.55 (d, J= 7.1 Hz, 3 H), 1.02 (d, J = 7.1 Hz, 1.5 H), 0.86 (d, J = 7.1 Hz, 1.5H), 0.57 (br s, 1.5 H), 0.46 (br s, 1.5 H) 84: (S)-3-(2-((S)-1-(5- δ8.16-8.12 (m, 2 H), 7.80 (d, J = 9.1 Hz, HRMS(B) bromo-6- 1 H), 7.72 (s,1 H), 7.56 (dd, J = 8.8, 1.8 m/z methoxynaphthalen-2- Hz, 1 H), 7.37 (d,J = 9.1 Hz, 1 H), 7.32 (d, 485.1184 yl)ethylamino)pyrimidin-4- J = 5.7Hz, 1 H), 5.18 (q, J = 6.7 Hz, 1 H), (M + H)⁺ yl)-4-isopropyloxazolidin-4.60-4.54 (m, 1 H), 4.28 (t, J = 8.8 Hz, 1 2-one H), 4.19 (dd, J = 9.1,3.0 Hz, 1 H), 3.99 (s, 3 H), 1.72 (br s, 1 H), 1.61 (d, J = 7.1 Hz, 3H), 0.39 (br d, J = 6.6 Hz, 3 H), 0.43 (br d, J = 6.1 Hz, 3 H) 85:(S)-3-(2-((R)-1-(4- 8.09 (d, J = 5.9 Hz, 1 H), 7.38-7.33 (m, 3 HRMS(B)fluorophenyl)ethylami- H), 7.04-6.98 (m, 2 H), 4.96 (q, J = 6.7 m/zno)pyrimidin-4-yl)-4- Hz, 1 H), 4.48 (br s, 1 H), 4.35-4.25 (m, 2345.1725 isopropyloxazolidin-2-one H), 2.64 (dtd, J = 14, 7.1, 3.5 Hz, 1H), (M + H)⁺ 1.50 (d, J = 6.6 Hz, 3 H), 0.98 (d, J = 7.1 Hz, 3 H), 0.85(d, J = 7.0 Hz, 3 H) 86: (S)-4-isopropyl-3-(2- 8.12 (d, J = 5.8 Hz, 1H), 7.77 (d, J = 8.1 HRMS(B) ((R)-1-(2- Hz, 1 H), 7.66 (d, J = 8.1 Hz, 1H), 7.60 (t, m/z (trifluoromethyl)phenyl)eth- J = 7.6 Hz, 1 H),7.42-7.36 (m, 2 H), 5.58 395.1706 ylamino)pyrimidin-4- (q, J = 6.7 Hz, 1H), 4.70 (dt, J = 7.8, 3.7 (M + H)⁺ yl)oxazolidin-2-one Hz, 1 H),4.38-4.31 (m, 2 H), 2.58 (dtd, J = 14, 7.0, 3.8 Hz, 1 H), 1.50 (d, J =6.9 Hz, 3 H), 0.98 (d, J = 7.0 Hz, 3 H), 0.85 (d, J = 6.9 Hz, 3 H) 87:(R)-4-methyl-3-(2-((S)- HRMS(B) 1-(naphthalen-2- m/zyl)ethylamino)pyrimidin-4- 425.1967 yl)-4-phenyloxazolidin-2- (M + H)⁺one 88: (S)-3-(2-((S)-1-(4- 8.12 (d, J = 5.8 Hz, 1 H), 7.35-7.31 (m, 3HRMS(B) fluorophenyl)ethylami- H), 7.03-6.97 (m, 2 H), 5.03 (q, J = 7.1m/z no)pyrimidin-4-yl)-4- Hz, 1 H), 4.66-4.63 (br m, 1 H), 4.35-345.1724 isopropyloxazolidin-2-one 4.27 (m, 2 H), 1.85 (br s, 1 H), 1.49(d, J = (M + H)⁺ 7.0 Hz, 3 H), 0.71 (br s, 3 H), 0.60 (br s, 3 H) 89:(R)-4-methyl-4-phenyl- (CDCl₃) 8.12 (d, J = 5.8 Hz, 1 H), 7.43 (d, J =HRMS(B) 3-(2-((S)-1- 5.8 Hz, 1 H) 7.32-7.20 (m, 8 H), 6.99 m/zphenylethylamino)pyrimidin- (br s, 2 H), 5.20 (br s, 1 H), 4.33 (br s, 1375.1822 4-yl)oxazolidin-2-one H), 4.32-4.27 (m, 2 H), 2.20 (s, 3 H),(M + H)⁺ 1.41 (d, J = 6.8 Hz, 3 H) 90: (S)-4-isopropyl-3-(2- 8.11 (d, J= 5.8 Hz, 1 H), 7.33 (d, J = 5.8 HRMS(B) ((S)-1-(2- Hz, 3 H), 7.20-7.16(m, 2 H), 6.95 (d, J = m/z methoxyphenyl)ethylami- 8.1 Hz, 1 H),6.86-6.82 (m, 1 H), 5.28 (q, 357.1924 no)pyrimidin-4- J = 7.1 Hz, 1 H),4.63 (br s, 1 H), 4.35- (M + H)⁺ yl)oxazolidin-2-one 4.26 (m, 2 H), 3.87(s, 3 H), 1.86 (br s, 1 H), 1.46 (d, J = 6.9 Hz, 3 H), 0.69 (br s, 3 H),0.56 (br s, 3 H) 91: (S)-3-(2-(1- 8.08 (d, J = 5.8 Hz, 1 H), 7.82-7.78(m, 4 HRMS(B) (naphthalen-2- H), 7.52 (dd, J = 8.6, 1.5 Hz, 1 H), 7.45-m/z yl)ethylamino)pyrimidin-4- 7.38 (m, 2 H), 7.29 (d, J = 5.8 Hz, 1 H),335.1509 yl)oxazolidin-2-one 5.23 (q, J = 6.9 Hz, 1 H), 4.46-4.33 (m, 2(M + H)⁺ H), 4.21-4.15 (m, 1 H), 3.93-3.86 (m, 1 H), 1.61 (d, J = 7.1Hz, 3 H) 92: (S)-4-isopropyl-3-(2- (CDCl₃) 15.12 (br s, 1 H), 9.23 (brs, 1 H), HRMS(B) ((S)-1-(3- 7.67-7.56 (m, 1 H), 7.24 (dd, J = 8, 8 Hz,m/z methoxyphenyl)ethylami- 1 H), 6.92-6.72 (m, 3 H), 5.04-4.86 (m,371.2082 no)-6-methylpyrimidin-4- 1 H), 4.72-4.51 (m, 1 H), 4.42-4.25(m, (M + H)⁺ yl)oxazolidin-2-one 2 H), 3.81 (s, 3 H), 2.56 (s, 3 H),1.90- hydrochloride 1.76 (m, 1 H), 1.64 (br s, 3 H), 0.73 (d, J = 8 Hz,3 H), 0.64 (d, J = 8 Hz, 3 H) 93: (S)-4-isopropyl-3-(6- (CDCl₃)7.57-7.19 (m, 6 H), 5.05-4.86 HRMS(B) methyl-2-((S)-1- (m, 1 H),4.63-4.09 (m, 3 H), 2.561/2.49 m/z phenylethylamino)pyrimidin- (2 x s, 3H), 1.91-1.70 (m, 1 H), 1.62/ 341.1982 4-yl)oxazolidin-2-one 1.54 (2 xd, 3 H), 0.75-0.45 (m, 6 H) (M + H)⁺ 94: (S)-3-(2-(((S)-3- (DMSO-d₆)8.11 (d, J = 5.5 Hz, 1 H), 7.39- HRMS(B) methylbutan-2- 7.32 (m, 2 H),7.31-7.19 (m, 4 H), 6.95- m/z yl)amino)pyrimidin-4-yl)-4- 6.82 (m, 1 H),5.83-5.73 (m, 1 H), 4.82 327.1822 phenyloxazolidin-2-one (t, J = 8.5 Hz,1 H), 4.15 (br s., 1 H), 1.37- (M + H)⁺ 1.21 (m, 1 H), 0.97 (d, J = 7.0Hz, 3 H), 0.58 (br s., 3 H), 0.47 (br s., 3 H) 95:(S)-5,5-dimethyl-3-(2- (DMSO-d₆) 8.10 (d, J = 5.5 Hz, 1 H), 7.39-HRMS(B) (((S)-3-methylbutan-2- 7.32 (m, 2 H), 7.31-7.23 (m, 2 H), 7.18m/z yl)amino)pyrimidin-4-yl)-4- (br. s, 1 H), 6.93-6.79 (m, 1 H), 5.43(s, 1 355.2123 phenyloxazolidin-2-one H), 1.62 (s, 3 H), 1.30-1.14 (m, 1H), 0.96 (M + H)⁺ (d, J = 6.5 Hz, 3 H), 0.90 (s, 3 H), 0.54 (d, J = 5.0Hz, 3 H), 0.43 (d, J = 5.0 Hz, 3 H) 96: 3-(2-(((3r,5r,7r)- (DMSO-d₆)8.11 (br s, 1 H), 7.15 (br s, 1 HRMS(B) adamantan-1- H), 4.52-4.36 (m, 2H), 4.09 (br s, 2 H), m/z ylmethyl)amino)pyrimidin- 3.03 (br s, 2 H),1.92 (br s, 3 H), 1.74- 329.1971 4-yl)oxazolidin-2-one 1.31 (m, 12 H)(M + H)⁺ 97: (S)-4-isopropyl-3-(2- 8.14 (d, J = 5.8 Hz, 1 H), 7.59 (d, J= 8.1 HRMS(B) ((S)-1-(4- Hz, 2 H), 7.51 (d, J = 8.1 Hz, 2 H), 7.36 (d,m/z (trifluoromethyl)phenyl)eth- J = 5.8 Hz, 1 H), 5.08 (q, J = 6.9 Hz,1 H), 395.1686 ylamino)pyrimidin-4- 4.59 (br s, 1 H), 4.33-4.25 (m, 2H), 1.57 (M + H)⁺ yl)oxazolidin-2-one (br s, 1 H), 1.54 (d, J = 7.1 Hz,3 H), 0.60 (br s, 3 H), 0.53 (br s, 3 H) 98: 3-((S)-1-(4-((S)-4- 8.14(d, J = 5.8 Hz, 1 H), 7.69-7.65 (m, 2 HRMS(B) isopropyl-2-oxooxazolidin-H), 7.58-7.56 (m, 1 H), 7.48 (t, J = 7.7 m/z 3-yl)pyrimidin-2- Hz, 1 H),7.37 (d, J = 5.8 Hz, 1 H), 5.09 (q, 352.1764 ylamino)ethyl)benzonitrileJ = 7.1 Hz, 1 H), 4.64 (br s, 1 H), 4.35- (M + H)⁺ 4.27 (m, 2 H), 1.74(br s, 1 H), 1.52 (d, J = 7.1 Hz, 3 H), 0.71 (br s, 3 H), 0.60 (br s, 3H) 99: (S)-3-(2-((S)-1-(3- 8.14 (d, J = 5.8 Hz, 1 H), 7.36 (d, J = 5.8HRMS(B) chlorophenyl)ethylami- Hz, 1 H), 7.32 (br s, 1 H), 7.29-7.23 (m,2 m/z no)pyrimidin-4-yl)-4- H), 7.20-7.17 (m, 1 H), 5.02 (q, J = 6.9361.1424 isopropyloxazolidin-2-one Hz, 1 H), 4,63 (br s, 1 H), 4.34-4.27(m, 2 (M + H)⁺ H), 1.82 (br s, 1 H), 1.50 (d, J = 7.1 Hz, 3 H), 0.70 (brs, 3 H), 0.59 (br s, 3 H) 100: (4R)-5,5-dimethyl-4- 8.07 (d, J = 5.8 Hz,0.5 H), 8.06 (d, J = 5.8 HRMS(B) phenyl-3-(2-(1-(4- Hz, 0.5 H),7.41-7.37 (m, 2 H), 7.34- m/z (piperidin-1- 7.26 (m, 2 H), 7.19-7.14 (m,3 H), 6.95- 472.2715 yl)phenyl)ethylamino)pyrimidin- 6.89 (m, 2 H),6.81-6.78 (m, 1 H), 5.46 (M + H)⁺ 4-yl)oxazolidin-2- (s, 0.5 H), 5.25(s, 0.5 H), 4.73-4.68 (m, one 0.5 H), 4.60-4.55 (m, 0.5 H), 3.12-3.07(m, 4 H), 1.73-1.68 (m, 4 H), 1.65 (s, 1.5 H), 1.61-1.57 (m, 2 H), 1.54(s, 1.5 H), 1.41 (d, J = 6.9 Hz, 1.5 H), 1.14 (d, J = 6.9 Hz, 1.5 H),0.99 (d, J = 4.7 Hz, 3 H) 101: (S)-4-isopropyl-3-(2- 8.15 (d, J = 5.8Hz, 1 H), 7.74 (d, J = 8.1 HRMS(B) ((S)-1-(2- Hz, 1 H), 7.69 (d, J = 8.1Hz, 1 H), 7.58 (t, m/z (trifluoromethyl)phenyl)eth- J = 7.6 Hz, 1 H),7.42-7.35 (m, 2 H), 5.35 395.1682 ylamino)pyrimidin-4- (q, J = 6.6 Hz, 1H), 4.65 (dt, J = 8.0, 3.8 (M + H)⁺ yl)oxazolidin-2-one Hz, 1 H),4.35-4.26 (m, 2 H), 1.76 (br s, 1 H), 1.52 (d, J = 6.6 Hz, 3 H), 0.64(br d, J = 5.5 Hz, 3 H), 0.58 (br d, J = 6.3 Hz, 3 H) 102:4,4-dimethyl-3-(2-(1- (CDCl₃) 8.22 (d, J = 5.8 Hz, 1 H), 7.87 (s, 1HRMS(B) (1-phenyl-1H-pyrazol-4- H), 7.69-7.65 (m, 3 H), 7.48-7.43 (m, 2m/z yl)ethylamino)pyrimidin-4- H), 7.35-7.28 (m, 2 H), 5.34 (br s, 1 H),379.1890 yl)oxazolidin-2-one 5.24-5.17 (m, 1 H), 4.09-4.05 (m, 2 H),(M + H)⁺ 1.74 (s, 3 H), 1.64 (d, J = 7.1 Hz, 3 H), 1.58 (s, 3 H) 103:(S)-3-(2- (DMSO-d₆) 8.13 (d, J = 5.5 Hz, 1 H), 7.20 HRMS(B)(((3S,5S,7S)-adamantan- (br s., 1 H), 7.17 (d, J = 5.5 Hz, 1 H), 4.69-m/z 1- 4.63 (m, 1 H), 4.44-4.33 (m, 2 H), 3.11- 371.2448ylmethyl)amino)pyrimidin- 2.85 (m, 2 H), 2.54 (br s, 1 H), 1.92 (br (M +H)⁺ 4-yl)-4- s., 3 H), 1.70-1.53 (m, 6 H), 1.47 (br s., 6isopropyloxazolidin-2-one H), 0.93 (d, J = 7.0 Hz, 3 H), 0.78 (d, J =6.5 Hz, 3 H); 104: (S)-3-(2-(((S)-1- (DMSO-d₆) 8.09 (d, J = 5.5 Hz, 1H), 7.40- HRMS(B) cyclohexylethyl)ami- 7.32 (m, 2 H), 7.32-7.23 (m, 3H), 6.83 m/z no)pyrimidin-4-yl)-5,5- (d, J = 9.0 Hz, 1 H), 5.42 (s, 1H), 3.36 (br 395.2446 dimethyl-4- s, 1 H), 1.72-1.23 (m, 9 H), 1.02-0.82(M + H)⁺ phenyloxazolidin-2-one (m, 10 H), 0.62 (s, 1 H), 0.20-0.04 (m,1 H) 105: (S)-3-(2-(((S)-1- (DMSO-d₆) 8.13 (d, J = 5.8 Hz, 1 H), 7.19-HRMS(B) cyclohexylethyl)ami- 7.09 (m, 2 H), 4.68 (br s, 1 H), 4.41- m/zno)pyrimidin-4-yl)-4- 4.33 (m, 2 H), 3.77 (br s, 1 H), 2.47 (br s, 1333.2288 isopropyloxazolidin- H), 1.76-1.58 (m, 5 H), 1.43-1.35 (m, 1(M + H)⁺ 2-one H), 1.15-1.04 (m, 6 H), 0.97-0.88 (m, 5 H), 0.77 (d, J =6.8 Hz, 3 H); 106: (4S)-4-isopropyl-3-(2- (DMSO-d₆) 8.19 (d, J = 5.6 Hz,1 H), 7.30- HRMS(B) ((1-phenoxypropan-2- 7.24 (m, 3 H), 7.18 (br s, 1H), 6.96- m/z yl)amino)pyrimidin-4- 6.85 (m, 3 H), 4.70-4.52 (m, 1 H),4.39- 357.1921 yl)oxazolidin-2-one 4.19 (m, 3 H), 4.12-4.00 (m, 1 H),3.92- (M + H)⁺ 3.78 (m, 1 H), 2.46 (br s, 1 H), 1.29-1.21 (m, 3 H),0.93-0.58 (m, 6 H) 107: (S)-3-(2-(((R)-1- (DMSO-d₆) 8.09 (d, J = 5.6 Hz,1 H), 7.38- HRMS(B) cyclohexylethyl)ami- 7.12 (m, 6 H), 6.71 (br s, 1H), 5.36 (s, 1 m/z no)pyrimidin-4-yl)-5,5- H), 1.77-1.56 (m, 9 H),1.31-1.05 (m, 4 395.2440 dimethyl-4- H), 0.92 (s, 6 H), 0.48 (br s., 2H) (M + H)⁺ phenyloxazolidin-2-one 108: (S)-3-(5-chloro-2- (CDCl₃) 8.29(s, 1 H), 7.84-7.74 (m, 4 H), HRMS(B) ((S)-1-(naphthalen-2- 7.49-7.43(m, 3 H), 5.76 (br s, 1 H), 5.17- m/z yl)ethylamino)pyrimidin-4- 5.10(m, 1 H), 4.39-4.30 (m, 1 H), 4.31 411.1588 yl)-4-isopropyloxazolidin-(t, J = 8.1 Hz, 1 H), 4.09-4.05 (m, 1 H), (M + H)⁺ 2-one 1.66 (d, J =7.0 Hz, 3 H), 1.40-1.30 (m, 1 H), 0.52 (d, J = 6.1 Hz, 3 H), 0.27 (br s,3 H) 109: 4-((S)-1-(4-((S)-4- 8.14 (d, J = 5.8 Hz, 1 H), 7.68-7.66 (m, 2HRMS(B) isopropyl-2-oxooxazolidin- H), 7.52 (d, J = 8.1 Hz, 3 H), 7.36(d, J = m/z 3-yl)pyrimidin-2- 5.9 Hz, 1 H), 5.08 (q, J = 7.1 Hz, 1 H),4.61 352.1775 ylamino)ethyl)benzonitrile (br s, 1 H), 4.34-4.26 (m, 2H), 1.60 (br s, (M + H)⁺ 1 H), 1.52 (d, J = 7.1 Hz, 3 H), 0.65 (br s, 3H), 0.58 (br s, 3 H) 110: (S)-4,4-dimethyl-3-(2- (CDCl₃) 8.10 (d, J =5.8 Hz, 1 H), 8.01 (d, J = HRMS(B) (1-(naphthalen-1- 8.6 Hz, 1 H),7.81-7.78 (m, 1 H), 7.66 m/z yl)ethylamino)pyrimidin-4- (d, J = 8.1 Hz,1 H), 7.52 (d, J = 6.6 Hz, 1 363.1822 yl)oxazolidin-2-one H), 7.48-7.39(m, 2 H), 7.36-7.32 (m, 1 (M + H)⁺ H), 7.19-7.18 (m, 1 H), 5.66 (br s, 2H), 3.78-3.69 (m, 2 H), 1.65 (s, 3 H), 1.64 (s, 3H), 1.35 (br s, 3 H)111: (R)-3-(2-((S)-1-(4- 8.09 (d, J = 5.7 Hz, 1 H), 7.41-7.07 (m,HRMS(B) fluorophenyl)ethylami- 10 H), 5.21 (s, 3 H), 4.96 (q, J = 7.1Hz, 1 m/z no)pyrimidin-4-yl)-5,5- H), 1.50 (s, 3 H), 1.24 (d, J = 7.1Hz, 3 H), 407.188 dimethyl-4- 0.98 (s, 3 H) (M + H)⁺phenyloxazolidin-2-one 112: 4-(1-(4-((S)-4- 8.13 (d, J = 5.8 Hz, 0.5 H),8.11 (d, J = 5.8 HRMS(B) isopropyl-2-oxooxazolidin- Hz, 0.5 H),7.85-7.80 (m, 2 H), 7.51 (d, J = m/z 3-yl)pyrimidin-2- 8.6 Hz, 1 H),7.49 (d, J = 8.6 Hz, 1 H), 406.1553 ylamino)ethyl)benzenesulfonamide7.36 (d, J = 5.7 Hz, 0.5 H), 7.35 (d, J = 5.7 (M + H)⁺ Hz, 0.5 H), 5.09(q, J = 6.9 Hz, 0.5 H), 5.03- 4.97 (br m, 0.5 H), 4.61 (br s, 0.5 H),4.33-4.24 (m, 2.5 H), 2.66-2.58 (m, 0.5 H), 1.62 (br s, 0.5 H), 1.532(d, J = 7.1 Hz, 1.5 H), 1.527 (d, J = 7.1 Hz, 1.5 H), 0.98 (d, J = 7.0Hz, 1.5 H), 0.84 (d, J = 7.0 Hz, 1.5 H), 0.67 (br s, 1.5 H), 0.56 (br s,1.5 H) 113: (S)-3-(2-((S)-1-(4- 8.11 (d, J = 5.8 Hz, 1 H), 7.33 (d, J =5.8 HRMS(B) hydroxyphenyl)ethylami- Hz, 1 H), 7.12 (d, J 8.1 Hz, 2 H),6.72- m/z no)pyrimidin-4-yl)-4- 6.68 (m, 2 H), 4.95 (q, J = 6.9 Hz, 1H), 343.1776 isopropyloxazolidin-2-one 4.69-4.65 (m, 1 H), 4.35-4.28 (m,2 H), (M + H)⁺ 1.47 (d, J = 7.1 Hz, 3 H), 0.75 (br s, 3 H), 0.62 (br s,3 H) 114: (S)-3-(2-(1- (CDCl₃) 8.14 (d, J = 5.8 Hz, 1 H), 7.24 (d, J =HRMS(B) cyclohexylethylami- 5.8 Hz, 1 H), 5.08 (br s, 1 H), 4.10 (s, 2m/z no)pyrimidin-4-yl)-4,4- H), 3.87 (q, J = 7.0 Hz, 1 H), 1.83-1.68319.2132 dimethyloxazolidin-2-one (m, 6 H), 1.75 (s, 3 H), 1.74 (s, 3H), 1.48 (M + H)⁺ (dddd, J = 12, 8.7, 5.7, 2.8 Hz, 1 H), 1.28- 1.03 (m,4 H), 1.17 (d, J = 6.8 Hz, 3 H) 115: (S)-3-(5-fluoro-2-((S)- (CDCl₃)8.15 (d, J = 3.5 Hz, 1 H), 7.83- HRMS(B) 1-(naphthalen-2- 7.72 (m, 4 H),7.49-7.42 (m, 3 H), 5.06- m/z yl)ethylamino)pyrimidin-4- 5.03 (m, 1 H),4.35-4.28 (m, 2 H), 4.10- 395.1884 yl)-4-isopropyloxazolidin- 4.08 (m, 1H), 1.65 (d, J = 7.0 Hz, 3 H), (M + H)⁺ 2-one 1.33-1.26 (m, 1 H), 0.38(br s, 3 H), 0.14 (br s, 3 H) 116: (S)-3-(5-chloro-2- (DMSO-d₆)8.39-8.31 (m, 2 H), 7.35- HRMS(B) ((S)-1- 7.32 (m, 2 H), 7.28 (t, J =7.8 Hz, 2 H), m/z phenylethylamino)pyrimidin- 7.17 (t, J = 7.8 Hz, 1 H),4.89-4.82 (m, 1 361.1431 4-yl)-4- H), 4.49-4.45 (m, 2 H), 4.16 (br s, 1H), (M + H)⁺ isopropyloxazolidin-2-one 1.42 (d, J = 7.0 Hz, 3 H), 1.24(br s, 1 H), 0.86-0.78 (m, 3 H), 0.48 (br s, 3 H) 117:(S)-3-(2-((S)-1-(4- 8.16 (d, J = 5.8 Hz, 1 H), 7.36 (d, J = 5.8 HRMS(B)bromo-3,5- Hz, 1 H), 6.64 (s, 2 H), 5.00-4.95 (m, 1 m/zdimethoxyphenyl)ethylami- H), 4.58 (br s, 1 H), 4.33-4.23 (m, 2 H),465.1134 no)pyrimidin-4-yl)-4- 3.79 (s, 6 H), 1.54 (d, J = 7.0 Hz, 3 H),(M + H)⁺ isopropyloxazolidin-2-one 0.55 (br s, 6 H) 118:(4S)-3-(2-(1-(3,4- 8.12 (d, J = 5.8 Hz, 0.5 H), 8.10 (d, J = 5.8 HRMS(B)dimethoxyphenyl)ethylami- Hz, 0.5 H), 7.35-7.32 (m, 1 H), 6.97- m/zno)pyrimidin-4-yl)-4- 6.85 (m, 3 H), 5.00-4.91 (m, 1 H), 4.65 387.2035isopropyloxazolidin-2-one (br s, 0.5 H), 4.55 (br s, 0.5 H), 4.36-4.27(M + H)⁺ (m, 2 H), 3.80-3.79 (m, 6 H), 2.69-2.61 (m, 0.5 H), 1.87 (br s,0.5 H), 1.50 (d, J = 7.1 Hz, 3 H), 1.00 (d, J = 7.1 Hz, 1.5 H), 0.86 (d,J = 7.0 Hz, 1.5 H), 0.69 (br s, 1.5 H), 0.60 (br s, 1.5 H) 119:(S)-3-(2-(1-(6- (CDCl₃) 8.09 (d, J = 5.8 Hz, 1 H), 7.64- HRMS(B)methoxynaphthalen-2- 7.59 (m, 3 H), 7.36 (dd, J = 8.3, 1.8 Hz, 1 m/zyl)ethylamino)pyrimidin-4- H), 7.20-7.18 (m, 1 H), 7.07-7.03 (m, 2393.1925 yl)-4,4-dimethyloxazolidin- H), 5.56 (br s, 1 H), 5.07-5.03 (brm, 1 (M + H)⁺ 2-one H), 3.91-3.82 (m, 5 H), 1.61 (s, 3 H), 1.56 (d, J =6.8 Hz, 3 H), 0.97 (br s, 3 H) 120: (S)-5,5-dimethyl-3-(2- 8.09 (d, J =5.8 Hz, 1 H), 7.81-7.79 (m, 1 HRMS(B) ((S)-1-(naphthalen-2- H),7.74-7.68 (m, 2 H), 7.52 (br s, 1 H), m/z yl)ethylamino)pyrimidin-4-7.46-7.41 (m, 3 H), 7.18 (br s, 1 H), 7.02 439.2131yl)-4-phenyloxazolidin-2- (br s, 2 H), 6.99 (s, 3 H), 5.43 (s, 1 H),5.02 (M + H)⁺ one (q, 6.6 Hz, 1 H), 1.62 (s, 3 H), 1.53 (d, J = 6.6 Hz,3 H), 0.93 (s, 3 H) 121: (S)-3-(2-((S)-1-(4- 8.08 (d, J = 5.8 Hz, 1 H),7.44 (d, J = 5.8 HRMS(B) bromophenyl)ethylamino) Hz, 1 H), 7.29-7.24 (m,5 H), 7.06 (br s, 2 m/z pyrimidin-4-yl)-5,5- H), 6.92 (br s, 2 H), 5.44(s, 1 H), 4.88- 467.1088 dimethyl-4- 4.84 (m, 1 H), 1.63 (s, 3 H), 1.42(d, J = (M + H)⁺ phenyloxazolidin-2-one 7.1 Hz, 3 H), 0.95 (s, 3 H) 122:(S)-3-(2-((S)-1-(3- 8.07 (d, J = 5.8 Hz, 1 H), 7.42 (d, J = 5.8 HRMS(B)methoxyphenyl)ethylami- Hz, 1 H), 7.28-7.21 (m, 3 H), 7.11-7.08 m/zno)pyrimidin-4-yl)-5,5- (m, 3 H), 6.72 (dd, J = 8.3, 1.8 Hz, 1 H),419.2067 dimethyl-4- 6.66 (br s, 1 H), 6.62 (br s, 1 H), 5.46 (s, 1 (M +H)⁺ phenyloxazolidin-2-one H), 4.80-4.74 (m, 1 H), 3.73 (s, 3 H), 1.64(s, 3 H), 1.42 (d, J = 7.1 Hz, 3 H), 0.98 (s, 3 H) 123:(S)-3-(2-((S)-1-(4- 8.14 (d, J = 6.6 Hz, 1 H), 7.57 (d, J = 6.6 HRMS(B)fluoro-3- Hz, 1 H), 7.08-6.99 (m, 2 H), 6.88 (ddd, J = m/zmethoxyphenyl)ethylami- 8.5, 4.2, 2.0 Hz, 1 H), 5.07 (q, J = 7.1 Hz,375.1824 no)pyrimidin-4-yl)-4- 1 H), 4.68 (dt, J = 7.8, 3.7 Hz, 1 H),4.40- (M + H)⁺ isopropyloxazolidin-2-one 4.32 (m, 2 H), 3.86 (s, 3 H),1.99 (br s, 1 H), 1.57 (d, J = 7.1 Hz, 3 H), 0.75 (d, J = 7.1 Hz, 3 H),0.66 (d, J = 7.1 Hz, 3 H) 124: (S)-3-(2-((S)-1-(4- 8.10 (d, J = 5.8 Hz,1 H), 7.39 (d, J = 5.8 HRMS(B) bromophenyl)ethylamino) Hz, 1 H),7.29-7.26 (m, 2 H), 7.25-7.21 m/z pyrimidin-4-yl)-4- (m, 3 H), 7.12 (dd,J = 6.3, 2.8 Hz, 2 H), 439.0763 phenyloxazolidin-2-one 6.96 (d, J = 8.6Hz, 2 H), 5.80 (dd, J = 8.6, (M + H)⁺ 3.5 Hz, 1 H), 4.87 (q, J = 7.1 Hz,1 H), 4.79 (t, J = 8.6 Hz, 1 H), 4.20 (dd, J = 8.6, 3.5 Hz, 1 H), 1.43(d, J = 7.1 Hz, 3 H) 125: (4S)-4-isopropyl-3-(2- 8.215 (d, J = 6.1 Hz,0.5 H), 8.212 (d, J = HRMS(B) ((1-(3- 6.1 Hz, 0.5 H), 7.52 (t, J = 7.1Hz, 2 H), m/z morpholinophenyl)ethyl)ami- 7.46 (dd, J = 5.8, 3.8 Hz, 1H), 7.43-7.34 412.2342 no)pyrimidin-4- (m, 3 H), 5.86 (qd, J = 8.2, 4.0Hz, 1 H), (M + H)⁺ yl)oxazolidin-2-one 4.83-4.75 (m, 1 H), 4.42-4.33 (m,2 H), 2.62 (dtd, J = 14, 7.0, 3.8 Hz, 0.5 H), 2.28 (br s, 0.5 H), 1.02(d, J = 7.1 Hz, 1.5 H), 0.91 (d, J = 7.1 Hz, 1.5 H), 0.88 (d, J = 7.11Hz, 1.5 H), 0.73 (d, J = 7.1 Hz, 1.5 H) 126: (R)-3-(2-((S)-1-(6- 8.10(d, J = 5.6 Hz, 1 H), 7.69 (d, J = 9.1 HRMS(B) methoxynaphthalen-2- Hz,1 H), 7.72 (d, J = 8.6 Hz, 1 H), 7.62 (s, m/z yl)ethylamino)pyrimidin-4-1 H), 7.44-7.29 (m, 7 H), 7.20 (d, J = 2.5 441.1929yl)-4-phenyloxazolidin-2- Hz, 1 H), 7.11 (dd, J = 9.1, 2.5 Hz, 1 H),(M + H)⁺ one 5.55 (dd, J = 8.8, 3.8 Hz, 1 H), 4.80 (q, J = 7.1 Hz, 1 H),4.69 (t, J = 8.6 Hz, 1 H), 4.16 (dd, J = 8.6, 4.0 Hz, 1 H), 3.90 (s, 3H), 1.28 (d, J = 7.1 Hz, 3 H) 127: (S)-4,4-dimethyl-3-(2- (CDCl₃) 8.20(d, J = 5.8 Hz, 1 H), 7.84- HRMS(B) (1-(naphthalen-2- 7.79 (m, 4 H),7.51-7.43 (m, 3 H), 7.29 m/z yl)ethylamino)pyrimidin-4- (d, J = 5.8 Hz,1 H), 5.65 (br s, 1 H), 5.19- 363.1819 yl)oxazolidin-2-one 5.16 (br m, 1H), 3.98 (d, J = 8.1 Hz, 1 H), (M + H)⁺ 3.91 (d, J = 8.1 Hz, 1 H), 1.70(s, 3 H), 1.66 (d, J = 6.9 Hz, 3 H), 1.02 (br s, 3 H) 128:4,4-dimethyl-3-(2-(1- (CDCl₃) 8.17 (d, J = 5.8 Hz, 1 H), 7.26- HRMS(B)(4-(piperidin-1- 7.22 (m, 3 H), 6.91 (d, J = 8.6 Hz, 2 H), m/zyl)phenyl)ethylami- 5.39 (br s, 1 H), 5.01-4.94 (m, 1 H), 4.04- 396.2396no)pyrimidin-4- 3.99 (m, 2 H), 3.14-3.12 (m, 4 H), 1.75- (M + H)⁺yl)oxazolidin-2- 1.69 (m, 8 H), 1.61-1.57 (m, 2 H), 1.55 one (d, J = 7.1Hz, 3 H), 1.34-1.29 (br m, 2 H) 129: (S)-3-(2-((S)-1-(3- 8.09 (d, J =5.8 Hz, 1 H), 7.36 (d, J = 5.8 HRMS(B) methoxyphenyl)ethylami- Hz, 1 H),7.26-7.16 (m, 5 H), 7.11 (t, J = m/z no)pyrimidin-4-yl)-4- 7.8 Hz, 3 H),6.74-6.66 (m, 3 H), 5.81 391.1771 phenyloxazolidin-2-one (dd, J = 8.6,3.5 Hz, 1 H), 4.86-4.79 (m, 2 (M + H)⁺ H), 4.23 (dd, J = 8.8, 3.8 Hz, 1H), 3.73 (s, 3 H), 1.44 (d, J 7.1 Hz, 3 H) 130: (4S)-3-(2-(1-(2,3- 8.11(d, J = 5.8 Hz, 0.5 H), 8.09 (d, J = 5.8 HRMS(B)dihydrobenzo[b][1,4]dioxin- Hz, 0.5 H), 7.34-7.33 (m, 1 H), 6.81- m/z6-yl)ethylamino)pyrimidin- 6.71 (m, 3 H), 4.93-4.88 (m, 1 H), 4.65385.1854 4-yl)-4- (br s, 0.5 H), 4.52 (br s, 0.5 H), 4.36-4.27 (M + H)⁺isopropyloxazolidin-2-one (m, 2 H), 4.20-4.17 (m, 4 H), 2.66 (dtd, J =14, 6.9, 3.5 Hz, 0.5 H), 1.99 (br s, 0.5 H), 1.456 (d, J = 7.1 Hz, 1.5H), 1.454 (d, J = 7.1 Hz, 1.5 H), 1.00 (d, J = 7.1 Hz, 1.5 H), 0.85 (d,J = 7.1 Hz, 1.5 H), 0.75 (br s, 1.5 H), 0.63 (br s, 1.5 H) 131:(4S)-4-isopropyl-3-(2- 8.545 (d, J = 6.1 Hz, 0.5 H), 8.540 (d, J =HRMS(B) (1-(pyridin-3- 6.1 Hz, 0.5 H), 8.39 (dt, J = 4.9, 1.6 Hz, 1 m/zyl)ethylamino)pyrimidin-4- H), 8.13 (dd, J = 11, 5.7 Hz, 1 H), 7.86-328.1771 yl)oxazolidin-2-one 7.80 (m, 1 H), 7.40-7.36 (m, 2 H), 5.12(M + H)⁺ (q, J = 7.1 Hz, 0.5 H), 5.02 (m, 0.5 H), 4.65 (br s, 0.5 H),4.42 (br s, 0.5 H), 4.35-4.25 (m, 2 H), 2.67-2.62 (m, 0.5 H), 1.76 (brs, 0.5 H), 1.56 (d, J = 7.1 Hz, 1.5 H), 1.55 (d, J = 7.1 Hz, 1.5 H),0.99 (d, J = 7.1 Hz, 1.5 H), 0.85 (d, J = 7.1 Hz, 1.5 H), 0.70 (br s,1.5 H), 0.60 (br s, 1.5 H) 132: (S)-4-benzyl-3-(2- 8.17 (d, J = 5.5 Hz,1 H), 7.46 (d, J = 6.0 HRMS(B) (cyclopropylamino)pyrimidin- Hz, 1 H),7.32-7.18 (m, 4 H), 7.15 (d, J = m/z 4-yl)oxazolidin-2-one 7.0 Hz, 2 H),5.04-4.91 (m, 1 H) 5.39 (br 311.1515 s, 1 H), 4.25-4.11 (m, 2 H), 3.51(d, J = (M + H)⁺ 13.0 Hz, 1 H), 2.80 (dd, J = 13.3, 9.79 Hz, 1 H),2.76-2.69 (m, 1 H), 0.84-0.71 (m, 2 H), 0.60-0.47 (m, 2 H) 133:(S)-4-benzyl-3-(2- (CDCl₃) 8.18 (d, J = 5.5 Hz, 1 H), 7.48 (d, J =HRMS(B) (cyclohexylamino)pyrimidin- 6.0 Hz, 1 H), 7.42-7.31 (m, 3 H),7.26 m/z 4-yl)oxazolidin-2-one (d, J = 7.0 Hz, 2 H), 5.56 (br s, 1 H),5.02 353.1979 (ddd, J = 9.9, 3.6, 3.5 Hz, 1 H), 4.33-4.22 (M + H)⁺ (m, 2H), 3.96-3.83 (m, 1 H), 3.53 (d, J = 12.6 Hz, 1 H), 2.85 (dd, J = 13.3,9.8 Hz, 1 H), 1.89-1.75 (m, 2 H), 2.16-2.05 (m, 2 H), 1.73-1.63 (m, 1H), 1.52-1.26 (m, 7 H) 134: (S)-4-benzyl-3-(2- 8.17 (d, J = 5.8 Hz, 1H), 7.38 (d, J = 5.8 HRMS(B) (benzylamino)pyrimidin-4- Hz, 1 H),7.36-7.30 (m, 2 H), 7.30-7.11 m/z yl)oxazolidin-2-one (m, 6 H), 7.02 (brs, 2 H), 4.95 (br s, 1 H), 361.1669 4.76-4.65 (m, 1 H), 4.65-4.55 (m, 1H), (M + H)⁺ 4.30 (t, J = 8.4 Hz, 1 H), 4.26-4.18 (m, 1 H), 3.05 (br s,1 H), 2.84 (br s, 1 H) 135: (S)-4-benzyl-3-(2- (CDCl₃) 8.22 (d, J = 5.5Hz, 1 H), 7.48 (d, J = HRMS(B) (((R)-1- 5.5 Hz, 1 H), 7.42-7.29 (m, 8H), 7.19 m/z phenylethyl)amino)pyrimidin- (d, J = 7.0 Hz, 2 H), 5.62 (brs, 1 H), 5.15 375.1817 4-yl)oxazolidin-2-one (t, J = 6.8 Hz, 1 H), 4.77(br s, 1 H), 4.25- (M + H)⁺ 4.16 (m, 2 H), 3.45 (dd, J = 13.8, 3.3 Hz, 1H), 2.94 (dd, J = 13.6, 9.0 Hz, 1 H), 1.61 (d, J = 7.0 Hz, 3 H) 136:(4S)-3-(2-(1-(1,3- 8.14 (d, J = 5.8 Hz, 0.5 H), 8.13 (d, J = 5.8 HRMS(B)dimethyl-1H-pyrazol-4- Hz, 0.5 H), 7.42 (s, 0.5 H), 7.35 (s, 0.5 H), m/zyl)ethylamino)pyrimidin-4- 7.35 (d, J = 5.7 Hz, 0.5 H), 7.34 (d, J = 5.8345.2038 yl)-4-isopropyloxazolidin- Hz, 0.5 H), 5.10-5.00 (m, 1 H), 4.75(dq, (M + H)⁺ 2-one J = 7.8, 4.0 Hz, 1 H), 4.41-4.32 (m, 2 H), 3.76 (s,1.5 H), 3.74 (s, 1.5 H), 2.64-2.57 (m, 0.5 H), 2.41-2.32 (m, 0.5 H),2.18 (s, 3 H), 1.493 (d, J = 7.1 Hz, 1.5 H), 1.488 (d, J = 7.1 Hz, 1.5H), 0.97 (d, J = 7.1 Hz, 1.5 H), 0.88 (d, J = 7.1 Hz, 3 H), 0.78 (d, J =7.1 Hz, 1.5 H) 137: (S)-3-[2-((S)-1,3- (DMSO-d₆) 8.10 (m, 1 H), 7.34 (m,2 H), HRMS(B) dimethyl-butylamino)- 7.26 (m, 3 H), 7.17 (br s, 1 H),6.83 (s, 1 m/z pyrimidin-4-yl]-5,5- H), 5.39 (s, 1 H), 1.61 (s, 3 H),1.39 (s, 1 369.2297 dimethyl-4-phenyl- H), 1.26 (s, 1 H), 1.02 (m, 4 H),0.90 (s, 3 (M + H)⁺ oxazolidin-2-one H), 0.81 (s, 1 H), 0.71 (s, 3 H),0.41 (s, 3 H) 138: (S)-3-[2-((S)-2- (DMSO-d₆) 8.14 (d, J = 5.8 Hz, 1 H),7.17 HRMS(B) hydroxy-1-methyl- (d, J = 5.8 Hz, 1 H), 7.03 (br s, 1 H),4.67 m/z ethylamino)-pyrimidin-4- (br s, 1 H), 4.42-4.34 (m, 2 H), 3.96(br s, 307.2141 yl]-5,5-dimethyl-4-phenyl- 1 H), 2.46 (m, 1 H), 1.63 (m,1 H), 1.47 (m, (M + H)⁺ oxazolidin-2-one 1 H), 1.21 (m, 1 H), 1.09 (d, J= 6.3 Hz, 3 H), 0.89 (d, J = 7.3 Hz, 3 H), 0.87 (d, J = 6.5 Hz, 3 H),0.84 (d, J = 6.5 Hz, 3 H), 0.77 (d, J = 6.8 Hz, 3 H) 139:(S)-4,4-dimethyl-3-(2-(1- (CDCl₃) 8.08 (d, J = 5.8 Hz, 1 H), 7.27-HRMS(B) phenylethylamino)pyrimidin- 7.20 (m, 4 H), 7.17 (d, J = 5.6 Hz,1 H), m/z 4-yl)oxazolidin-2-one 7.15-7.11 (m, 1 H), 5.42 (br s, 1 H),4.94- 313.1668 4.87 (m, 1 H), 3.92-3.86 (m, 2 H), 1.58 (M + H)⁺ (s, 3H), 1.47 (d, J = 6.9 Hz, 3 H), 1.06 (br s, 3 H) 140: (S)-3-(2-((S)-1-(4-(CDCl₃) 8.17 (d, J = 5.8 Hz, 1 H), 7.45- HRMS(B) fluorophenyl)ethylami-7.31 (m, 4 H), 7.28-7.24 (m, 2 H), 7.09- m/zno)pyrimidin-4-yl)-4-methyl-4- 7.06 (m, 2 H), 7.01-6.95 (m, 2 H), 5.21393.1729 phenyloxazolidin-2-one (br s, 1 H), 4.20 (s, 2 H), 4.13 (br s,1 H), (M + H)⁺ 1.65 (br s, 3 H), 1.13 (d, J = 6.8 Hz, 3 H) 141:(4S)-4-methyl-4- (CDCl₃) 8.14 (d, J = 5.8 Hz, 0.35 H), 8.12 HRMS(B)phenyl-3-(2-(1-(4- (d, J = 5.8 Hz, 0.65 H), 7.42-7.27 (m, 6 m/z(piperidin-1- H), 7.04 (d, J = 8.6 Hz, 0.65 H), 6.91- 458.2551yl)phenyl)ethylami- 6.82 (m, 3.35 H), 5.16 (br s, 0.35 H), 5.02 (M + H)⁺no)pyrimidin-4-yl)oxazolidin- (br s, 0.65 H), 4.30 (s, 1.3 H), 4.22 (s,0.7 2-one H), 4.19 (br s, 1 H), 3.16-3.13 (m, 4 H), 2.20 (s, 1.95 H),1.79-1.70 (br m, 5.05 H), 1.62-1.56 (m, 2 H), 1.37 (d, J = 6.8 Hz, 1.95H), 1.06 (d, J = 6.3 Hz, 1.05 H) 142: (S)-4-benzyl-3-(2-(((S)-1- 8.15(d, J = 5.77 Hz, 1 H), 7.40-7.30 (m, HRMS(B)phenylethyl)amino)pyrimidin- 3 H), 7.25-7.13 (m, 5 H), 7.07 (t, J = 7.0m/z 4-yl)oxazolidin-2-one Hz, 1 H), 6.91 (br s, 2 H), 5.13 (q, J = 7.0375.1817 Hz, 1 H), 5.01 (t, J = 7.4 Hz, 1 H), 4.34 (t, J = (M + H)⁺ 8.5Hz, 1 H), 4.20 (dd, J = 8.9, 2.4 Hz, 1 H), 2.64 (br s, 1 H), 2.47 (br s,1 H), 1.54 (d, J = 7.3 Hz, 3 H) 143: (R)-4-benzyl-3-(2- (CDCl₃) 8.19 (d,J = 5.0 Hz, 1 H), 7.62 (d, J = HRMS(B) (cyclopropylamino)pyrimidin- 6.0Hz, 1 H), 7.41-7.29 (m, 4 H), 7.26- m/z 4-yl)oxazolidin-2-one 7.19 (m, 2H), 6.42 (br s, 1 H), 5.07 (t, J = 311.1516 8.3 Hz, 1 H), 4.30-4.24 (m,2 H), 3.60 (d, (M + H)⁺ J = 12.6 Hz, 1 H), 2.97-2.79 (m, 2 H), 0.95-0.81(m, 2 H), 0.75-0.62 (m, 2 H) 144: (R)-4-benzyl-3-(2- 8.12 (d, J = 6.0Hz, 1 H), 7.36-7.28 (m, 3 HRMS(B) (cycloheptylamino)pyrimidin- H),7.28-7.19 (m, 3 H), 5.15-5.05 (m, 1 m/z 4-yl)oxazolidin-2-one H), 4.37(t, J = 8.5 Hz, 1 H), 4.30-4.24 367.2134 (m, 1 H), 4.04 (br s., 1 H),3.09 (dd, J = (M + H)⁺ 13.6, 8.0 Hz, 1 H), 2.11-1.94 (m, 2 H), 1.78-1.48(m, 11 H) 145: (R)-4-benzyl-3-(2- (CDCl₃) 8.18 (d, J = 5.0 Hz, 1 H),7.48 (d, J = HRMS(B) (cyclohexylamino)pyrimidin- 6.0 Hz, 1 H), 7.42-7.29(m, 3 H), 7.26 m/z 4-yl)oxazolidin-2-one (d, J = 7.0 Hz, 2 H), 5.55 (brs, 1 H), 5.10- 353.1981 4.94 (m, 1 H), 4.33-4.22 (m, 2 H), 3.96- (M +H)⁺ 3.82 (m, 1 H), 3.53 (d, J = 12.1 Hz, 1 H), 2.85 (dd, J = 13.3, 9.8Hz, 1 H), 2.22- 2.01 (m, 2 H), 1.81 (td, J = 13.6, 4.0 Hz, 2 H), 1.68(dd, J = 9.0, 3.5 Hz, 1 H), 1.51- 1.22 (m, 6 H) 146: (R)-4-benzyl-3-(2-8.17 (d, J = 5.8 Hz, 1 H), 7.38 (d, J = 6.0 HRMS(B)(benzylamino)pyrimidin-4- Hz, 1 H), 7.35-7.30 (m, 2 H), 7.29-7.18 m/zyl)oxazolidin-2-one (m, 5 H), 7.15 (t, J = 7.3 Hz, 1 H), 7.02 (br361.1659 s, 2 H), 4.95 (br s, 1 H), 4.75-4.65 (m, 1 (M + H)⁺ H),4.65-4.56 (m, 1 H), 4.30 (t, J = 8.5 Hz, 1 H), 4.27-4.20 (m, 1 H), 3.05(br s, 1 H), 2.82 (br s, 1 H) 147: (R)-4-benzyl-3-(2- (CDCl₃) 8.21 (d, J= 5.5 Hz, 1 H), 7.50 (d, J = HRMS(B) (((R)-1- 6.0 Hz, 1 H), 7.43-7.29(m, 5 H), 7.28- m/z phenylethyl)amino)pyrimidin- 7.12 (m, 4 H), 7.00 (brs., 2 H), 5.97 (br s, 375.1822 4-yl)oxazolidin-2-one 1 H), 5.17 (t, J =6.8 Hz, 1 H), 5.03-4.89 (M + H)⁺ (m, 1 H), 4.28 (t, J = 8.5 Hz, 1 H),4.19 (dd, J = 9.0, 3.0 Hz, 1 H), 2.97 (br s, 1 H), 2.53 (br s, 1 H),1.63 (d, J = 7.0 Hz, 3 H) 148: (R)-4-benzyl-3-(2- (CDCl₃) 8.21 (d, J =6.0 Hz, 1 H), 7.49 (d, J = HRMS(B) (((S)-1- 5.5 Hz, 1 H), 7.44-7.29 (m,8 H), 7.19 m/z phenylethyl)amino)pyrimid (d, J = 6.5 Hz, 2 H), 5.69 (brs, 1 H),, 5.15 375.1816 in-4-yl)oxazolidin-2-one (t, J = 7.0 Hz, 1 H),4.76 (br s, 1 H), 4.24- (M + H)⁺ 4.16 (m, 2 H), 3.45 (dd, J = 13.8, 3.3Hz, 1 H), 2.94 (dd, J = 13.6, 9.5 Hz, 1 H), 1.61 (d, J = 7.0 Hz, 3 H)149: (S)-4-isopropyl-3-(5- (CDCl₃) 8.13 (s, 1 H), 7.35-7.28 (m, 4 H),HRMS(B) methyl-2-((S)-1- 7.24-7.20 (m, 1 H), 5.73 (br s, 1 H), 5.00- m/zphenylethylamino)pyrimidin- 4.92 (m, 1 H), 4.59-4.51 (m, 1 H), 4.38341.1974 4-yl)oxazolidin-2-one (t, J = 8.8 Hz, 1 H), 4.12 (t, J = 8.8Hz, 1 (M + H)⁺ H), 2.14 (s, 3 H), 1.55 (d, J = 6.5 Hz, 3 H), 1.44 (br s,1 H), 0.59 (d, J = 6.5 Hz, 3 H), 0.53 (d, J = 5.0 Hz, 3 H) 150:(S)-3-(5-fluoro-2-((S)- (CDCl₃) 8.18 (d, J = 3.0 Hz, 1 H), 7.32- HRMS(B)1- 7.28 (m, 4 H), 7.25-7.20 (m, 1 H), 5.64 m/zphenylethylamino)pyrimidin- (br s, 1 H), 4.92-4.87 (m, 1 H), 4.47-345.1724 4-yl)-4- 4.40 (m, 1 H), 4.39 (t, J = 8.5 Hz, 1 H), (M + H)⁺isopropyloxazolidin-2-one 4.17 (t, J = 8.6 Hz, 1 H), 1.86 (br s, 1 H),1.54 (d, J = 7.0 Hz, 3 H), 0.68-0.56 (m, 6 H) 151: (S)-4-isopropyl-3-(CDCl₃) 8.11 (s, 1 H), 7.24-7.20 (m, 1 H), HRMS(B) (2-((S)-1-(3-6.94-6.89 (m, 2H), 6.76 (dd, J = 7.6 Hz, J = m/z methoxyphenyl)ethylami-2.5 Hz, 1 H), 5.99 (br s, 1 H), 4.97 (quin, 371.2083 no)-5- J = 6.8 Hz,1 H), 4.58 (td, J = 8.8 Hz, J = (M + H)⁺ methylpyrimidin-4- 5.1 Hz, 1H), 4.39 (t, J = 8.8 Hz, 1 H), 4.13 yl)oxazolidin-2-one (t, J = 8.6 Hz,1 H), 3.80 (s, 3 H), 2.16 (s, 3 H), 1.62-1.56 (m, 1 H), 1.57 (d, J = 6.5Hz, 3 H), 0.64 (d, J = 7.1 Hz, 3 H), 0.59 (d, J = 7.1 Hz, 3 H) 152:(S)-4-isopropyl-3-(5- (CDCl₃) 8.13 (s, 1 H), 7.81-7.74 (m, 4 H), HRMS(B)methyl-2-((S)-1- 7.48-7.40 (m, 3 H), 5.87 (br s, 1 H), 5.17- m/z(naphthalen-2- 5.10 (m, 1 H), 4.42 (td, J = 8.7 Hz, J = 391.2135yl)ethylamino)pyrimidin-4- 4.8 Hz, 1 H), 4.29 (t, J = 8.8 Hz, 1 H), 4.02(M + H)⁺ yl)oxazolidin-2-one (t, J = 8.6 Hz, 1 H), 2.13 (s, 3 H), 1.64(d, J = 7.0 Hz, 3 H), 1.35-1.28 (m, 1 H), 0.42 (d, J = 7.1 Hz, 3 H),0.17 (d, J = 7.0 Hz, 3 H) 153: (S)-3-(5-fluoro-2-((S)- (CDCl₃) 8.16 (d,J = 2.5 Hz, 1 H), 7.23 (t, J = HR-MS 1-(3- 7.8 Hz, 1 H), 6.91-6.83 (m, 2H), 6.78- m/z (M + methoxyphenyl)ethylami- 6.74 (m, 1 H), 6.05 (br s, 1H), 4.86 (br s, H)⁺ no)pyrimidin-4-yl)-4- 1 H), 4.49-4.38 (m, 2 H), 4.19(t, J = 7.8 isopropyloxazolidin-2-one Hz, 1 H), 3.79 (s, 3 H), 1.54 (d,J = 8.0 Hz, 3 H), 1.32-1.25 (m, 1 H), 0.66-0.58 (m, 6 H) 154:(S)-4-methyl-3-(2- (CDCl₃) 8.17 (d, J = 5.8 Hz, 1 H), 7.84- HRMS(B)((S)-1-(naphthalen-2- 7.78 (m, 3 H), 7.55 (s, 1 H), 7.51-7.43 m/zyl)ethylamino)pyrimidin-4- (m, 5 H), 7.39-7.36 (m, 1 H), 7.29-7.25425.1972 yl)-4-phenyloxazolidin-2- (m, 3 H), 5.54 (br s, 1 H), 4.31 (brs, 1 H), (M + H)⁺ one 4.19-4.12 (m, 2 H), 1.84 (br s, 3 H), 1.24 (d, J =6.8 Hz, 3 H) 155: (S)-3-(2-((S)-1-(6- (CDCl₃) 8.18 (d, J = 5.8 Hz, 1 H),7.69 (t, J = HRMS(B) methoxynaphthalen-2- 7.8 Hz, 2 H), 7.47-7.41 (m, 4H), 7.38- m/z yl)ethylamino)pyrimidin-4- 7.34 (m, 1 H), 7.28-7.23 (m, 3H), 7.17- 455.2081 yl)-4-methyl-4- 7.13 (m, 2 H), 5.31 (br s, 1 H), 4.31(br s, 1 phenyloxazolidin-2-one H), 4.19-4.13 (m, 2 H), 3.94 (s, 3 H),1.56 (br s, 3 H), 1.20 (d, J = 6.6 Hz, 3 H) (M + H)⁺ 156:(S)-3-(2-((S)-1- (CDCl₃) 8.11 (d, J = 5.8 Hz, 1 H), 7.38- HRMS(B)cyclohexylethylami- 7.32 (m, 5 H), 7.29-7.25 (m, 1 H), 4.81 m/zno)pyrimidin-4-yl)-4-methyl- (br s, 1 H), 4.31-4.26 (m, 2 H), 3.16 (brs, 381.2280 4-phenyloxazolidin-2-one 1 H), 2.17 (s, 3 H), 1.77-1.57 (m,6 H), (M + H)⁺ 1.28-1.09 (m, 4 H), 0.99-0.85 (m, 2 H), 0.55 (br s, 2 H)157: (S)-3-[2-((S)-2- (DMSO-d₆) 8.13 (m, 1 H), 7.36 (m, 2 H), HRMS(B)hydroxy-1-methyl- 7.29 (m, 3 H), 7.19 (br s, 1 H), 6.65 (s, 1 m/zethylamino)-pyrimidin-4- H), 5.44 (s, 1 H), 4.30 (br s, 1 H), 2.95 (br343.1778 yl]-5,5-dimethyl-4-phenyl- s, 1 H), 2.77 (br s, 3 H), 1.61 (s,3 H), 1.25 (M + H)⁺ oxazolidin-2-one (s, 1 H), 1.04 (m, 3 H), 0.92 (s, 3H) 158: (S)-5,5-dimethyl-4- (DMSO-d₆) 8.10 (d, J = 5.5 Hz, 1 H), 7.37-HRMS(B) phenyl-3-[2-((S)-1,2,2- 7.33 (m, 2 H), 7.29-7.25 (m, 3 H), 7.20m/z trimethyl-propylamino)- (br s, 1 H), 6.75 (d, J = 10 Hz, 1 H), 5.42369.2277 pyrimidin-4-yl]-oxazolidin- (s, 1 H), 3.47 (m, 1 H), 1.62 (s, 3H), 0.96 (M + H)⁺ 2-one (d, J = 6.8 Hz, 3 H), 0.88 (s, 3 H), 0.46 (s, 9H) 159: (R)-3-(2-((S)-1- 8.11 (d, J = 6.1 Hz, 1 H), 8.04 (d, J = 8.6HRMS(B) (naphthalen-1- Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1 H), 7.74 (d, m/zyl)ethylamino)pyrimidin-4- J = 8.1 Hz, 1 H), 7.60-7.56 (m, 1 H), 7.53-411.1823 yl)-4-phenyloxazolidin-2- 7.49 (m, 1 H), 7.46-7.44 (m, 1 H),7.42- (M + H)⁺ one 7.31 (m, 5 H), 7.21-7.18 (m, 2 H), 5.52 (q, J = 6.9Hz, 1 H), 5.44 (dd, J = 8.8, 3.8 Hz, 1 H), 4.63 (t, J = 8.7 Hz, 1 H),4.10 (dd, J = 8.6, 4.0 Hz, 1 H), 1.33 (d, J = 7.1 Hz, 3 H) 160:(S)-4-isopropyl-3-[2- (DMSO-d₆) 8.14 (d, J = 5.5 Hz, 1 H), 7.16 HRMS(B)((S;-1,2,2-trimethyl- (d, J = 5.5 Hz, 1 H), 7.00 (br. s, 1 H), 4.73- m/zpropylamino)-pyrimidin-4- 4.66 (m, 1 H), 4.41-4.34 (m, 2 H), 3.92307.2130 yl]-oxazolidin-2-one (br s, 1 H), 2.46 (br s, 1 H), 1.05 (d, J= 6.8 (M + H)⁺ Hz, 3 H), 0.91 (d, J = 7.3 Hz, 3 H), 0.87 (s, 9 H), 0.77(d, J = 6.8 Hz, 3 H) 161: (S)-3-[2-((S)-1- (DMSO-d₆) 8.13 (d, J = 5.5Hz, 1 H), 7.17 HRMS(B) cyclopropyl-ethylamino)- (d, J = 5.5 Hz, 1 H),7.09 (br s, 1 H), 4.67- m/z pyrimidin-4-yl]-4-isopropyl- 4.63 (m, 1 H),4.37 (m, 2 H), 3.52-3.43 291.1812 oxazolidin-2-one (m, 1 H), 2.46 (br s,1 H), 1.19 (d, J = 6.8 (M + H)⁺ Hz, 3 H), 1.01-0.93 (m, 1 H), 0.89 (d, J= 7.0 Hz, 3 H), 0.77 (d, J = 6.8 Hz, 3 H), 0.41 (m, 1 H), 0.33 (m, 1 H),0.22 (br s, 1 H), 0.10 (br s, 1 H) 162: (S)-4-isopropyl-3-(2- 8.13 (d, J= 5.8 Hz, 1 H), 7.34-7.28 (m, 5 HRMS(B) ((S)-1-(4- H), 7.09-7.05 (m, 1H), 6.96-6.90 (m, 4 m/z phenoxyphenyl)ethylami- H), 5.06 (q, J = 7.1 Hz,1 H), 4.71-4.67 419.2081 no)pyrimidin-4- (m, 1 H), 4.37-4.28 (m, 2 H),2.08 (br s, 1 (M + H)⁺ yl)oxazolidin-2-one H), 1.52 (d, J = 7.1 Hz, 3H), 0.76 (d, J = 7.1 Hz, 3 H), 0.67 (d, J = 7.1 Hz, 3 H) 163:(S)-3-(2-((S)-1-(2,3- 8.12 (d, J = 5.6 Hz, 1 H), 7.32 (d, J = 5.6HRMS(B) dihydrobenzofuran-5- Hz, 1 H), 7.17 (s, 1 H), 7.04-7.02 (m, 1m/z yl)ethylamino)pyrimidin-4- H), 6.63 (d, J = 8.1 Hz, 1 H), 4.98 (q, J= 369.1915 yl)-4-isopropyloxazolidin- 7.1 Hz, 1 H), 4.69-4.65 (m, 1 H),4.51- (M + H)⁺ 2-one 4.47 (m, 2 H), 4.36-4.27 (m, 2 H), 3.16- 3.12 (m, 2H), 2.09 (br s, 1 H), 1.48 (d, J = 7.0 Hz, 3 H), 0.75 (d, J = 7.0 Hz, 3H), 0.65 (d, J = 7.1 Hz, 3 H) 164: (S)-3-(2-((S)-1-(4- 8.12 (d, J = 5.8Hz, 1 H), 7.34-7.31 (m, 3 HRMS(B) tert- H), 7.24-7.21 (m, 2 H), 5.02 (q,J = 7.1 m/z butylphenyl)ethylamino)pyrimidin- Hz, 1 H), 4.66-4.63 (m, 1H), 4.35-4.25 383.2449 4-yl)-4- (m, 2 H), 1.95 (br s, 1 H), 1.50 (d, J =7.0 (M + H)⁺ isopropyloxazolidin-2-one Hz, 3 H), 1.29 (s, 9 H), 0.69 (d,J = 7.0 Hz, 3 H), 0.58 (d, J = 6.9 Hz, 3 H) 165: (S)-3-[2-((S)-1-(DMSO-d₆) 8.10 (d, J = 5.5 Hz, 1 H), 7.37- HRMS(B)cyclopropyl-ethylamino)- 7.33 (m, 2 H), 7.30-7.24 (m, 3 H), 7.15 m/zpyrimidin-4-yl]-5,5- (br s, 1 H), 7.00 (br s, 1 H), 5.37 (s, 1 H),353.1974 dimethyl-4-phenyl- 2.82 (br s, 1 H), 1.61 (s, 3 H), 1.07 (d, J= (M + H)⁺ oxazolidin-2-one 6.5 Hz, 3 H), 0.89 (s, 3 H), 0.65 (br s, 1H), 0.17 (br s, 1 H), 0.00 (br s, 1 H), −0.23 (br s, 1 H), −0.65 (br s,1 H) 166: (S)-3-(5-fluoro-2-((S)- (DMSO-d₆) 8.36 (br s, 1 H), 7.95 (brs, 1 HRMS(B) 1-(4- H), 7.24 (d, J = 8.5 Hz, 2 H), 6.82 (d, J = m/zmethoxyphenyl)ethylami- 9.0 Hz, 2 H), 6.05 (br s, 1 H), 4.77 (br s, 1375.1815 no)pyrimidin-4-yl)-4- H), 4.54-4.45 (m, 2 H), 4.24 (br s, 1 H),(M + H)⁺ isopropyloxazolidin-2-one 3.70 (s, 3 H), 1.38 (d, J = 7.0 Hz, 3H), 1.26-1.22 (m, 1 H), 0.66-0.47 (m, 6 H) 167: (R)-5,5-dimethyl-4- 8.08(d, J = 5.8 Hz, 1 H), 7.42-7.38 (m, 3 HRMS(B) phenyl-3-(2-((S)-1- H),7.35-7.27 (m, 5 H), 7.22-7.17 (m, 3 m/z phenylethylamino)pyrimidin- H),5.18 (s, 1 H), 4.62-4.57 (m, 1 H), 1.51 389.1975 4-yl)oxazolidin-2-one(s, 3 H), 1.19 (d, J = 7.0 Hz, 3 H), 0.98 (s, (M + H)⁺ 3 H) 168:(R)-5,5-dimethyl-3- 8.10 (d, J = 5.8 Hz, 1 H), 7.82 (d, J = 8.1 HRMS(B)(2-((S)-1-(naphthalen-2- Hz, 3 H), 7.73 (s, 1 H), 7.48-7.33 (m, 7 m/zyl)ethylamino)pyrimidin-4- H), 7.19 (d, J = 7.1 Hz, 2 H), 5.07 (s, 1 H),439.2132 yl)-4-phenyloxazolidin-2- 4.74 (q, J = 6.6 Hz, 1 H), 1.32 (d, J= 6.9 (M + H)⁺ one Hz, 3 H), 1.29 (s, 3 H), 0.92 (s, 3 H) 169:(R)-3-(2-((S)-1-(4- δ 8.10 (d, J = 5.8 Hz, 1 H), 7.41-7.28 (m, HRMS(B)fluoro-3- 6 H), 7.02-6.97 (m, 2 H), 6.82 (ddd, J = m/zmethoxyphenyl)ethylami- 8.2, 4.4, 2.0 Hz, 1 H), 5.61 (dd, J = 8.6, 4.0409.1677 no)pyrimidin-4-yl)-4- Hz, 1 H), 4.77 (t, J = 8.6 Hz, 1 H), 4.65(q, (M + H)⁺ phenyloxazolidin-2-one J = 7.1 Hz, 1 H), 4.19 (dd, J = 9.1,4.0 Hz, 1 H), 3.83 (s, 3 H), 1.20 (d, J = 7.9 Hz, 3 H)

Example 170(4S)-4-isopropyl-3-(2-(2,2,2-trifluoro-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one

A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(163 mg, 0.674 mmol), 2,2,2-trifluoro-1-phenylethanamine (624 mg, 3.56mmol, 5.3 equiv) and p-toluenesulfonic acid monohydrate (321 mg, 1.69mmol, 2.5 equiv) in n-BuOH (3 mL) was heated at 110° C. for 2 h andtreated with additional p-toluenesulfonic acid monohydrate (321 mg, 1.69mmol, 2.5 equiv), then heated at 110° C. for 1½ h. After cooling, thesolid reaction mixture was treated with MeCN, sonicated and filtered.The filtrated was concentrated and purified by silica gel columnchromatography (EtOAc/Heptane 0 to 30%) to give(4S)-4-isopropyl-3-(2-(2,2,2-trifluoro-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one(65 mg) in 25% yield. ¹H NMR (400 MHz, CD₃OD) δ 8.215 (d, J=6.1 Hz,0.5H), 8.212 (d, J=6.1 Hz, 0.5H), 7.52 (t, J=7.1 Hz, 2H), 7.46 (dd,J=5.8, 3.8 Hz, 1H), 7.43-7.34 (m, 3H), 5.86 (qd, J=8.2, 4.0 Hz, 1H),4.83-4.75 (m, 1H), 4.42-4.33 (m, 2H), 2.62 (dtd, J=14, 7.0, 3.8 Hz,0.5H), 2.28 (br s, 0.5H), 1.02 (d, J=7.1 Hz, 1.5H), 0.91 (d, J=7.1 Hz,1.5H), 0.88 (d, J=7.11 Hz, 1.5H), 0.73 (d, J=7.1 Hz, 1.5H); HRMS(B) m/z381.1545 (M+H)⁺.

Examples 171 and 172

A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(106 mg, 0.439 mmol) and 1-(3-fluorophenyl)ethanamine (196 mg, 1.41mmol, 3.21 equiv) in DMSO (1 mL) was heated at 110° C. for 1½ h. Thereaction mixture was diluted with EtOAc (8 mL) and washed with water (30mL). After separation, the aqueous phase was extracted with EtOAc (3×8mL). Combined organics were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%)provided(S)-3-(2-((R)-1-(3-fluorophenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneand(S)-3-(2-((S)-1-(3-fluorophenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.

Example 171 first eluted product (28 mg)¹H NMR (400 MHz, CD₃OD) δ 8.11(d, J=5.8 Hz, 1H), 7.36-7.27 (m, 2H), 7.16 (d, J=7.6 Hz, 1H), 7.07 (dt,J=10, 2.0 Hz, 1H), 6.92-6.88 (m, 1H), 4.98-4.93 (m, 1H), 4.42 (br s,1H), 4.32 (dd, J=9.1, 2.8 Hz, 1H), 4.26 (t, J=8.7 Hz, 1H), 2.64 (dtd,J=14, 7.1, 3.5 Hz, 1H), 1.50 (d, J=7.0 Hz, 3H), 0.98 (d, J=7.1 Hz, 3H),0.85 (d, J=7.0 Hz, 3H); HRMS(B) m/z 345.1729 (M+H)⁺.

Example 172 second eluted product (22 mg)¹H NMR (400 MHz, CD₃OD) δ 8.13(d, J=5.7 Hz, 1H), 7.36 (d, J=5.8 Hz, 1H), 7.29 (td, J=8.1, 6.1 Hz, 1H),7.13 (d, J=7.6 Hz, 1H), 7.06-7.04 (m, 1H), 6.94-6.87 (m, 1H), 5.03 (q,J=7.1 Hz, 1H), 4.64 (br s, 1H), 4.34-4.26 (m, 2H), 1.79 (br s, 1H), 1.50(d, J=7.1 Hz, 3H), 0.70 (br s, 3H), 0.58 (br s, 3H); HRMS(B) m/z345.1727 (M+H)⁺.

Examples 173 and 174

A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(90 mg, 0.37 mmol), iPr₂NEt (0.455 mL, 2.61 mmol, 7.0 equiv) and1-(biphenyl-4-yl)ethanamine hydrochloride (87 mg, 0.37 mmol) in DMSO (1mL) was heated at 110° C. for 2 h. The reaction mixture was diluted withEtOAc (8 mL) and washed with water (30 mL). After separation, theaqueous phase was extracted with EtOAc (3×8 mL). Combined organics weredried over Na₂SO₄, filtered and concentrated. Silica gel columnchromatography (EtOAc/Heptane 10 to 50%) provided(S)-3-(2-((R)-1-(biphenyl-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneand(S)-3-(2-((S)-1-(biphenyl-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.

Example 173 first eluted product (17 mg)¹H NMR (400 MHz, CD₃OD) δ 8.11(d, J=5.8 Hz, 1H), 7.59-7.54 (m, 4H), 7.43-7.28 (m, 6H), 5.01 (q, J=6.8Hz, 1H), 4.49 (br s, 1H), 4.32 (dd, J=9.1, 3.0 Hz, 1H), 4.26 (t, J=8.6Hz, 1H), 2.67 (dtd, J=14, 7.0, 3.5 Hz, 1H), 1.55 (d, J=7.1 Hz, 3H), 1.01(d, J=7.1 Hz, 3H), 0.86 (d, J=7.0 Hz, 3H); HRMS(B) m/z 403.2141 (M+H)⁺.

Example 174 second eluted product (21 mg)¹H NMR (400 MHz, CD₃OD) δ 8.14(d, J=5.8 Hz, 1H), 7.58-7.52 (m, 4H), 7.42-7.28 (m, 6H), 5.06 (q, J=7.1Hz, 1H), 4.63 (br s, 1H), 4.34-4.25 (m, 2H), 1.79 (br s, 1H), 1.55 (d,J=7.1 Hz, 3H), 0.65 (br s, 3H), 0.53 (br s, 3H); HRMS(B) m/z 403.2139(M+H)⁺.

Examples 175 and 176

A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(96 mg, 0.40 mmol) and 1-(4-chlorophenyl)ethanamine (204 mg, 1.31 mmol,3.3 equiv) in DMSO (1 mL) was heated at 110° C. for 3 h. The reactionmixture was diluted with EtOAc (8 mL) and washed with water (30 mL).After separation, the aqueous phase was extracted with EtOAc (3×8 mL).Combined organics were dried over Na₂SO₄, filtered and concentrated.Silica gel column chromatography (EtOAc/Heptane 10 to 50%) provided(S)-3-(2-((R)-1-(4-chlorophenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneand(S)-3-(2-((S)-1-(4-chlorophenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.

Example 175 first eluted product (32 mg)¹H NMR (400 MHz, CD₃OD) δ 8.10(d, J=5.8 Hz, 1H), 7.36-7.28 (m, 5H), 4.95 (q, J=6.7 Hz, 1H), 4.45 (brs, 1H), 4.35-4.26 (m, 2H), 2.64 (dtt, J=11, 7.0, 3.4 Hz, 1H), 1.50 (d,J=7.1 Hz, 3H), 0.98 (d, J=7.1 Hz, 3H), 0.85 (d, J=7.1 Hz, 3H); HRMS(B)m/z 361.1430 (M+H)⁺.

Example 176 second eluted product (40 mg)¹H NMR (400 MHz, CD₃OD) δ 8.13(d, J=5.7 Hz, 1H), 7.36-7.26 (m, 5H), 5.00 (q, J=7.1 Hz, 1H), 4.62 (brs, 1H), 4.34-4.26 (m, 2H), 1.77 (br s, 1H), 1.50 (d, J=7.1 Hz, 3H), 0.68(br s, 3H), 0.59 (br s, 3H); HRMS(B) m/z 361.1431 (M+H)⁺.

Examples 177 and 178

A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(93 mg, 0.38 mmol) and 1-(3,4-dichlorophenyl)ethanamine (73.1 mg, 0.385mmol, 1.0 equiv) in DMSO (1 mL) was heated at 110° C. for 1½ h. Thereaction mixture was diluted with EtOAc (8 mL) and washed with water (30mL). After separation, the aqueous phase was extracted with EtOAc (3×8mL). Combined organics were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%)provided(S)-3-(2-((R)-1-(3,4-dichlorophenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneand(S)-3-(2-((S)-1-(3,4-dichlorophenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.

Example 177 first eluted product (21 mg)¹H NMR (400 MHz, CD₃OD) δ 8.12(d, J=5.8 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.37(d, J=5.8 Hz, 1H), 7.28 (dd, J=8.6, 2.0 Hz, 1H), 4.94-4.88 (m, 1H), 4.43(br s, 1H), 4.35-4.26 (m, 2H), 2.68-2.60 (m, 1H), 1.50 (d, J=7.1 Hz,3H), 0.99 (d, J=7.1 Hz, 3H), 0.85 (d, J=7.1 Hz, 3H); HRMS(B) m/z395.1035 (M+H)⁺.

Example 178 second eluted product (28 mg)¹H NMR (400 MHz, CD₃OD) δ 8.15(d, J=5.8 Hz, 1H), 7.47-7.42 (m, 2H), 7.37 (d, J=5.8 Hz, 1H), 7.25 (dd,J=8.1, 2.0 Hz, 1H), 5.01-4.96 (m, 1H), 4.61 (br s, 1H), 4.34-4.26 (m,2H), 1.72 (br s, 1H), 1.50 (d, J=7.1 Hz, 3H), 0.67 (br s, 3H), 0.60 (brs, 3H); HRMS(B) m/z 395.1044 (M+H)⁺.

Examples 179 and 180

A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(86 mg, 0.36 mmol) and 1-(3-(1H-pyrrol-1-yl)phenyl)ethanamine (100 mg,0.537 mmol, 1.5 equiv) in DMSO (1 mL) was heated at 110° C. for 1½ h.The reaction mixture was diluted with EtOAc (8 mL) and washed with water(30 mL). After separation, the aqueous phase was extracted with EtOAc(3×8 mL). Combined organics were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%)provided(S)-3-(2-((R)-1-(3-(1H-pyrrol-1-yl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneand(S)-3-(2-((S)-1-(3-(1H-pyrrol-1-yl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.

Example 179 first eluted product (14 mg)¹H NMR (400 MHz, CD₃OD) δ 8.11(d, J=5.8 Hz, 1H), 7.45 (t, J=1.8 Hz, 1H), 7.39-7.29 (m, 3H), 7.23 (d,J=7.6 Hz, 1H), 7.13 (t, J=2.0 Hz, 2H), 6.25 (t, J=2.1 Hz, 2H), 5.03-4.97(m, 1H), 4.46 (br s, 1H), 4.31-4.20 (m, 2H), 2.64 (dtd, J=14, 7.0, 3.8Hz, 1H), 1.56 (d, J=7.1 Hz, 3H), 0.95 (d, J=7.1 Hz, 3H), 0.84 (d, J=7.0Hz, 3H); HRMS(B) m/z 392.2092 (M+H)⁺.

Example 180 second eluted product (10 mg)¹H NMR (400 MHz, CD₃OD) δ 8.14(d, J=5.7 Hz, 1H), 7.42 (br s, 1H), 7.38-7.28 (m, 3H), 7.20 (d, J=7.6Hz, 1H), 7.12 (t, J=2.3 Hz, 2H), 6.25 (t, J=2.0 Hz, 2H), 5.09 (q, J=6.9Hz, 1H), 4.64 (br s, 1H), 4.32-4.23 (m, 2H), 1.84 (br s, 1H), 1.55 (d,J=7.1 Hz, 3H), 0.54 (br s, 6H); HRMS(B) m/z 392.2090 (M+H)⁺.

Examples 181 and 182

A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(44 mg, 0.18 mmol) and 1-(4-(1H-pyrrol-1-yl)phenyl)ethanamine (33.9 mg,0.182 mmol, 1 equiv) in DMSO (1 mL) was heated at 110° C. for 2 h. Thereaction mixture was diluted with EtOAc (8 mL) and washed with water (30mL). After separation, the aqueous phase was extracted with EtOAc (3×8mL). Combined organics were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%)provided(S)-3-(2-((R)-1-(4-(1H-pyrrol-1-yl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneand(S)-3-(2-((S)-1-(4-(1H-pyrrol-1-yl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.

Example 181 first eluted product (18 mg)¹H NMR (400 MHz, CD₃OD) δ 8.11(d, J=5.8 Hz, 1H), 7.44-7.39 (m, 4H), 7.35 (d, J=5.9 Hz, 1H), 7.13 (t,J=2.2 Hz, 2H), 6.24 (t, J=2.0 Hz, 2H), 5.02-4.96 (m, 1H), 4.49 (br s,1H), 4.34-4.25 (m, 2H), 2.66 (dtd, J=14, 7.0, 3.3 Hz, 1H), 1.53 (d,J=7.1 Hz, 3H), 1.00 (d, J=7.1 Hz, 3H), 0.86 (d, J=7.1 Hz, 3H); HRMS(B)m/z 392.2089 (M+H)⁺.

Example 182 second eluted product (9 mg)¹H NMR (400 MHz, CD₃OD) δ 8.14(d, J=5.8 Hz, 1H), 7.39 (s, 4H), 7.35 (d, J=5.9 Hz, 1H), 7.12 (t, J=2.2Hz, 2H), 6.25 (t, J=2.0 Hz, 2H), 5.05 (q, J=7.1 Hz, 1H), 4.64 (br s,1H), 4.34-4.26 (m, 2H), 1.87 (br s, 1H), 1.53 (d, J=7.1 Hz, 3H), 0.68(br s, 3H), 0.57 (br s, 3H); HRMS(B) m/z 392.2082 (M+H)⁺.

Examples 183 and 184

A mixture of(4S)-3-(2-((1-(3,4-dimethoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one(example 118) was resolved on a column (AS-H 4.6×100 mm) using 30% iPrOHin CO₂ to give(S)-3-(2-((R)-1-(3,4-dimethoxyphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneand(S)-3-(2-((S)-1-(3,4-dimethoxyphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.

Example 183 first eluted product (13 mg)¹H NMR (400 MHz, CD₃OD) δ 8.11(d, J=5.8 Hz, 1H), 7.33 (d, J=5.8 Hz, 1H), 6.97 (br d, J=1.5 Hz, 1H),6.92-6.88 (m, 2H), 4.96 (q, J=6.7 Hz, 1H), 4.61-4.55 (m, 1H), 4.35-4.28(m, 2H), 3.803 (s, 3H), 3.800 (s, 3H), 2.63 (dtd, J=14, 7.0, 3.5 Hz,1H), 1.51 (d, J=7.1 Hz, 3H), 0.99 (d, J=7.1 Hz, 3H), 0.86 (d, J=7.1 Hz,3H); HRMS(B) m/z 387.2031 (M+H)⁺.

Example 184 second eluted product (10 mg)¹H NMR (400 MHz, CD₃OD) δ 8.13(d, J=5.8 Hz, 1H), 7.32 (d, J=5.7 Hz, 1H), 6.94 (br d, J=1.1 Hz, 1H),6.89-6.84 (m, 2H), 4.99 (q, J=7.1 Hz, 1H), 4.67-4.63 (m, 1H), 4.36-4.26(m, 2H), 3.79 (s, 6H), 2.01 (br s, 1H), 1.51 (d, J=7.1 Hz, 3H), 0.71 (d,J=7.1 Hz, 3H), 0.63 (d, J=7.0 Hz, 3H); HRMS(B) m/z 387.2029 (M+H)⁺.

Examples 185 and 186

A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(93 mg, 0.38 mmol) and 1-(4-(piperidin-1-yl)phenyl)ethanamine (410 mg,2.01 mmol, 5.2 equiv) in DMSO (1 mL) was heated at 110° C. for 2 h. Thereaction mixture was diluted with EtOAc (8 mL) and washed with water (30mL). After separation, the aqueous phase was extracted with EtOAc (3×8mL). Combined organics were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane 10 to100%) provided(4S)-4-isopropyl-3-(2-((1-(4-(piperidin-1-yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(57 mg) in 36% yield. A mixture of(4S)-4-isopropyl-3-(2-(1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-onewas resolved on a column (AD-H 4.6×100 mm) using 5 to 55% MeOH with 0.2%Et₂NH in CO₂ to give(S)-4-isopropyl-3-(2-((R)-1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-oneand(S)-4-isopropyl-3-(2-((S)-1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one.

Example 185 first eluted product (16 mg)¹H NMR (400 MHz, CD₃OD) δ 8.10(d, J=5.8 Hz, 1H), 7.31 (d, J=5.8 Hz, 1H), 7.24-7.20 (m, 2H), 6.94-6.91(m, 2H), 4.93 (q, J=7.1 Hz, 1H), 4.58-4.54 (m, 1H), 4.34-4.27 (m, 2H),3.11-3.08 (m, 4H), 2.63 (dtd, J=14, 7.1, 3.5 Hz, 1H), 1.73-1.67 (m, 4H),1.60-1.54 (m, 2H), 1.49 (d, J=7.1 Hz, 3H), 0.98 (d, J=7.1 Hz, 3H), 0.86(d, J=7.1 Hz, 3H); HRMS(B) m/z 410.2555 (M+H)⁺.

Example 186 second eluted product (16 mg)¹H NMR (400 MHz, CD₃OD) δ 8.11(d, J=5.8 Hz, 1H), 7.31 (d, J=5.8 Hz, 1H), 7.20-7.16 (m, 2H), 6.93-6.89(m, 2H), 4.98 (q, J=6.9 Hz, 1H), 4.69-4.65 (m, 1H), 4.36-4.26 (m, 2H),3.10-3.07 (m, 4H), 2.07 (br s, 1H), 1.73-1.67 (m, J=4H), 1.60-1.54 (m,2H), 1.48 (d, J=7.1 Hz, 3H), 0.75 (d, J=7.0 Hz, 3H), 0.63 (d, J=7.1 Hz,3H); HRMS(B) m/z 410.2556 (M+H)⁺.

Examples 187 and 188

A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(96 mg, 0.40 mmol) and 1-(1-phenyl-1H-pyrazol-4-yl)ethanamine (387 mg,2.97 mmol, 5.2 equiv) in DMSO (1.5 mL) was heated at 110° C. for 1½ h.The reaction mixture was diluted with EtOAc (8 mL) and washed with water(30 mL). After separation, the aqueous phase was extracted with EtOAc(3×8 mL). Combined organics were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane 20 to 80%)provided(S)-4-isopropyl-3-(2-((R)-1-(1-phenyl-1H-pyrazol-4-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-oneand(S)-4-isopropyl-3-(2-((S)-1-(1-phenyl-1H-pyrazol-4-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one.

Example 187 first eluted product (13 mg)¹H NMR (400 MHz, CD₃OD) δ 8.16(d, J=5.8 Hz, 1H), 8.10 (s, 1H), 7.70-7.66 (m, 3H), 7.48-7.43 (m, 2H),7.37 (d, J=5.7 Hz, 1H), 7.32-7.28 (m, 1H), 5.20 (q, J=6.6 Hz, 1H), 4.75(dt, J=7.7, 4.0 Hz, 1H), 4.40-4.33 (m, 2H), 2.61 (dtt, J=11, 7.0, 3.6Hz, 1H), 1.60 (d, J=6.9 Hz, 3H), 0.96 (d, J=7.1 Hz, 3H), 0.87 (d, J=6.9Hz, 3H); HRMS(B) m/z 393.2029 (M+H)⁺.

Example 188 second eluted product (11 mg)¹H NMR (400 MHz, CD₃OD) δ 8.17(d, J=5.8 Hz, 1H), 8.03 (s, 1H), 7.68-7.62 (m, 3H), 7.48-7.43 (m, 2H),7.37 (d, J=5.8 Hz, 1H), 7.32-7.27 (m, 1H), 5.19 (q, J=7.1 Hz, 1H), 4.74(dt, J=8.5, 3.6 Hz, 1H), 4.38-4.29 (m, 2H), 2.37-2.33 (m, 1H), 1.60 (d,J=7.1 Hz, 3H), 0.79 (d, J=7.1 Hz, 3H), 0.73 (s, J=7.1 Hz, 3H); HRMS(B)m/z 393.2039 (M+H)⁺.

Examples 189 and 190

A solution of (R)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one(97 mg, 0.35 mmol), 1-(biphenyl-4-yl)ethanamine hydrochloride (304 mg,1.30 mmol, 3.7 equiv) and iPr₂NEt (0.307 mL, 1.76 mmol, 5.0 equiv) inDMSO (1 mL) was heated at 110° C. for 1½ h and at 130° C. for 20 h. Thereaction mixture was diluted with EtOAc (8 mL) and washed with water (30mL). After separation, the aqueous phase was extracted with EtOAc (3×8mL). Combined organics were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%)provided(R)-3-(2-((R)-1-(biphenyl-4-yl)ethylamino)pyrimidin-4-yl)-4-phenyloxazolidin-2-oneand(R)-3-(2-((S)-1-(biphenyl-4-yl)ethylamino)pyrimidin-4-yl)-4-phenyloxazolidin-2-one.

Example 189 first eluted product (12 mg)¹H NMR (400 MHz, CD₃OD) δ 8.10(d, J=5.8 Hz, 1H), 7.58-7.55 (m, 2H), 7.44-7.37 (m, 6H), 7.33-7.28 (m,1H), 7.24-7.14 (m, 6H), 5.84 (dd, J=8.6, 3.5 Hz, 1H), 4.94 (q, J=6.7 Hz,1H), 4.81 (t, J=8.6 Hz, 1H), 4.22 (dd, J=8.8, 3.8 Hz, 1H), 1.49 (d,J=7.1 Hz, 3H); HRMS(B) m/z 437.1981 (M+H)⁺.

Example 190 second eluted product (11 mg)¹H NMR (400 MHz, CD₃OD) δ 8.10(d, J=5.8 Hz, 1H), 7.60-7.54 (m, 4H), 7.44-7.28 (m, 11H), 5.60 (dd,J=8.6, 4.0 Hz, 1H), 4.77-4.69 (m, 2H), 4.19 (dd, J=8.6, 4.0 Hz, 1H),1.25 (d, J=7.0 Hz, 3H); HRMS(B) m/z 437.1971 (M+H)⁺.

Examples 191 and 192

(4S)-3-(2-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one(example 130, 52 mg) was resolved on a column (IA 4.6×100 mm) using 40%iPrOH in CO₂ to give(S)-3-(2-((R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneand(S)-3-(2-((S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.

Example 191 first eluted product (7 mg)¹H NMR (400 MHz, CD₃OD) δ 8.10(d, J=5.6 Hz, 1H), 7.33-7.31 (m, 1H), 6.82-6.74 (m, 3H), 4.88 (q, J=7.1Hz, 1H), 4.58-4.53 (m, 1H), 4.34-4.28 (m, 2H), 4.21-4.18 (m, 4H), 2.63(td, J=7.1, 3.5 Hz, 1H), 1.47 (d, J=7.1 Hz, 3H), 0.99 (d, J=7.1 Hz, 3H),0.86 (d, J=7.1 Hz, 3H); HRMS(B) m/z 385.1875 (M+H)⁺.

Example 192 second eluted product (19 mg)¹H NMR (400 MHz, CD₃OD) δ 8.12(d, J=5.8 Hz, 1H), 7.33-7.31 (m, 1H), 6.78-6.72 (m, 3H), 4.93 (q, J=6.7Hz, 1H), 4.68-4.64 (m, 1H), 4.36-4.27 (m, 2H), 2.08 (br s, 1H), 1.47 (d,J=7.1 Hz, 3H), 0.76 (d, J=7.1 Hz, 3H), 0.65 (d, J=7.1 Hz, 3H); HRMS(B)m/z 385.1873 (M+H)⁺.

Examples 193 and 194

A solution of (R)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one(83 mg, 0.30 mmol) and 1-(3,4-dichlorophenyl)ethanamine (260 mg, 1.37mmol, 4.5 equiv) in DMSO (1.5 mL) was heated at 110° C. for 1½ h. Thereaction mixture was diluted with EtOAc (8 mL) and washed with water (30mL). After separation, the aqueous phase was extracted with EtOAc (3×8mL). Combined organics were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%)provided(R)-3-(2-((R)-1-(3,4-dichlorophenyl)ethylamino)pyrimidin-4-yl)-4-phenyloxazolidin-2-oneand(R)-3-(2-((S)-1-(3,4-dichlorophenyl)ethylamino)pyrimidin-4-yl)-4-phenyloxazolidin-2-one.

Example 193 first eluted product (13 mg)¹H NMR (400 MHz, CD₃OD) δ 8.11(d, J=5.6 Hz, 1H), 7.44-7.38 (m, 5H), 7.35-7.31 (m, 1H), 7.27-7.25 (m,2H), 7.18 (dd, J=8.3, 2.3 Hz, 1H), 5.53 (dd, J=8.8, 3.8 Hz, 1H), 4.76(t, J=8.8 Hz, 1H), 4.59-4.53 (m, 1H), 4.18 (dd, J=8.8, 4.3 Hz, 1H), 1.22(d, J=7.1 Hz, 3H); HRMS(B) m/z 429.0899 (M+H)⁺.

Example 194 second eluted product (26 mg)¹H NMR (400 MHz, CD₃OD) δ 8.13(d, J=5.6 Hz, 1H), 7.41 (d, J=6.1 Hz, 1H), 7.25-7.18 (m, 5H), 7.09-7.06(m, 2H), 6.95-6.93 (m, 1H), 5.78 (dd, J=8.6, 3.5 Hz, 1H), 4.89 (q, J=6.7Hz, 1H), 4.79 (t, J=8.6 Hz, 1H), 4.18 (dd, J=8.8, 3.8 Hz, 1H), 1.42 (d.J=7.1 Hz, 3H); HRMS(B) m/z 429.0887 (M+H)⁺.

Examples 195 and 196

(4S)-4-methyl-4-phenyl-3-(2-(1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one(example 141, 51 mg) was resolved on a column (IA 4.6×100 mm) using 45%MeOH in CO₂ to give(S)-4-methyl-4-phenyl-3-(2-((S)-1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-oneand(S)-4-methyl-4-phenyl-3-(2-((R)-1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one.

Example 195 first eluted product (21.6 mg)¹H NMR (400 MHz, CDCl₃) δ 8.13(d, J=5.8 Hz, 1H), 7.41 (d, J=5.8 Hz, 1H), 7.36-7.33 (m, 4H), 7.32-7.26(m, 1H), 6.88-6.82 (br m, 4H), 5.01 (br s, 1H), 4.30 (s, 2H), 3.16-3.13(m, 4H), 2.20 (s, 3H), 1.76-1.57 (br m, 6H), 1.37 (d, J=6.7 Hz, 3H);HRMS(B) m/z 458.2558 (M+H)⁺.

Example 196 second eluted product (20.6 mg)¹H NMR (400 MHz, CDCl₃) δ8.14 (d, J=5.8 Hz, 1H), 7.50-7.27 (m, 6H), 7.05 (d, J=8.6 Hz, 2H),6.96-6.92 (br m, 2H), 5.27 (br s, 1H), 4.22 (s, 2H), 3.21-3.13 (m, 4H),1.78-1.76 (br m, 7H), 1.63-1.57 (br m, 2H), 1.07 (d, J=6.1 Hz, 3H);HRMS(B) m/z 458.2559 (M+H)⁺.

Examples 197 and 198

4,4-dimethyl-3-(2-(1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one(example 183, 70 mg) was resolved on a column (IA 4.6×100 mm) using 40%MeOH in CO₂ to give(S)-4,4-dimethyl-3-(2-(1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-oneand(R)-4,4-dimethyl-3-(2-(1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one.

Example 197 first eluted product (23.8 mg)¹H NMR (400 MHz, CDCl₃) δ 8.17(br d, J=5.8 Hz, 1H), 7.28-7.23 (m, 3H), 6.93 (br d, J=7.7 Hz, 2H), 5.44(br s, 1H), 4.97 (br s, 1H), 4.05-3.99 (m, 2H), 3.15-3.12 (m, 4H),1.77-1.70 (m, 8H), 1.61-1.54 (m, 5H), 1.32 (br s, 2H); HRMS(B) m/z396.2413 (M+H)⁺.

Example 198 second eluted product (22.3 mg)¹H NMR (400 MHz, CDCl₃) δ8.17 (br d, J=5.5 Hz, 1H), 7.28-7.23 (m, 3H), 6.94 (br d, J=7.5 Hz, 2H),5.48 (br s, 1H), 4.97 (br s, 1H), 4.05-3.99 (m, 2H), 3.15-3.12 (m, 4H),1.77-1.70 (m, 8H), 1.61-1.54 (m, 5H), 1.31 (br s, 2H); HRMS(B) m/z396.2410 (M+H)⁺.

Examples 199 and 200

A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(98 mg, 0.41 mmol), 1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethanaminehydrochloride (502 mg, 2.08 mmol, 5.1 equiv) and iPr₂NEt (0.637 mL, 3.65mmol, 9.0 equiv) in DMSO (1.5 mL) was heated at 110° C. for 16 h. Thereaction mixture was diluted with EtOAc (8 mL) and washed with water (30mL). After separation, the aqueous phase was extracted with EtOAc (3×8mL). Combined organics were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane 20 to 80%)provided(S)-3-(2-((R)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneand(S)-3-(2-((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.

Example 199 first eluted product (49 mg)¹H NMR (400 MHz, CD₃OD) δ 8.16(d, J=5.8 Hz, 1H), 8.06 (s, 1H), 7.71-7.67 (m, 3H), 7.37 (d, J=5.9 Hz,1H), 7.22-7.16 (m, 2H), 5.20 (q, J=6.6 Hz, 1H), 4.74 (dt, J=7.6, 3.8 Hz,1H), 4.40-4.34 (m, 2H), 2.60 (dtd, J=14, 7.0, 3.5 Hz, 1H), 1.59 (d,J=6.9 Hz, 3H), 0.96 (d, J=7.1 Hz, 3H), 0.87 (d, J=7.1 Hz, 3H); HRMS(B)m/z 411.1943 (M+H)⁺.

Example 200 second eluted product (27 mg)¹H NMR (400 MHz, CD₃OD) δ 8.17(d, J=5.8 Hz, 1H), 8.00 (s, 1H), 7.69-7.66 (m, 2H), 7.61 (s, 1H), 7.37(d, J=5.9 Hz, 1H), 7.22-7.16 (m, 2H), 5.19 (q, J=6.7 Hz, 1H), 4.73 (dt,J=8.1, 3.5 Hz, 1H), 4.39-4.30 (m, 2H), 2.38-2.31 (m, 1H), 1.59 (d, J=6.8Hz, 3H), 0.79 (d, J=7.1 Hz, 3H), 0.73 (d, J=7.0 Hz, 3H); HRMS(B) m/z411.1937 (M+H)⁺.

Examples 201 and 202

A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(93 mg, 0.38 mmol), 1-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)ethanaminehydrochloride (514 mg, 2.03 mmol, 5.3 equiv) and iPr₂NEt (0.605 mL, 3.46mmol, 9.0 equiv) in DMSO (1.5 mL) was heated at 110° C. for 16 h. Thereaction mixture was diluted with EtOAc (8 mL) and washed with water (30mL). After separation, the aqueous phase was extracted with EtOAc (3×8mL). Combined organics were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 70%)provided(S)-4-isopropyl-3-(2-((R)-1-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-oneand(S)-4-isopropyl-3-(2-((S)-1-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one.

Example 201 first eluted product (17 mg)¹H NMR (400 MHz, CD₃OD) δ 8.15(d, J=5.8 Hz, 1H), 7.98 (s, 1H), 7.63 (s, 1H), 7.58-7.54 (m, 2H), 7.37(d, J=5.8 Hz, 1H), 7.03-6.99 (m, 2H), 5.19 (q, J=7.1 Hz, 1H), 4.75 (dt,J=7.7, 4.0 Hz, 1H), 4.40-4.33 (m, 2H), 3.83 (s, 3H), 2.61 (dtd, J=14,7.1, 3.5 Hz, 1H), 1.59 (d, J=7.1 Hz, 3H), 0.96 (d, J=7.1 Hz, 3H), 0.87(d, J=7.1 Hz, 3H); HRMS(B) m/z 423.2138 (M+H)⁺.

Example 202 second eluted product (18 mg)¹H NMR (400 MHz, CD₃OD) δ 8.16(d, J=5.8 Hz, 1H), 7.91 (s, 1H), 7.58-7.53 (m, 3H), 7.37 (d, J=5.9 Hz,1H), 7.03-6.99 (m, 2H), 5.18 (q, J=6.7 Hz, 1H), 4.76-4.72 (m, 1H),4.39-4.30 (m, 2H), 3.83 (s, 3H), 2.31 (br s, 1H), 1.59 (d, J=7.1 Hz,3H), 0.80 (d, J=7.1 Hz, 3H), 0.73 (d, J=7.1 Hz, 3H); HRMS(B) m/z 423.214(M+H)⁺.

Examples 203 and 204

4-(4-methoxyphenyl)-5,5-dimethyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one(example 54, 62 mg) was resolved in on a column (AD-H 4.6×100 mm) with30% MeOH modified with 0.2% Et₂NH in CO₂ to give(S)-4-(4-methoxyphenyl)-5,5-dimethyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-oneand(R)-4-(4-methoxyphenyl)-5,5-dimethyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one.

Example 203 first eluted product (22 mg)¹H NMR (400 MHz, CDCl₃) δ 8.12(br d, J=5.6 Hz, 1H), 7.53 (d, J=5.7 Hz, 1H), 7.37-7.24 (m, 5H),7.08-7.05 (m, 2H), 6.92-6.89 (m, 2H), 5.47 (br s, 1H), 5.02 (br s, 1H),4.66 (br s, 1H), 3.83 (s, 3H), 1.50 (s, 3H), 1.28 (br d, J=6.6 Hz, 3H),1.01 (s, 3H); HRMS(B) m/z 419.208 (M+H)⁺.

Example 204 second eluted product (22.2 mg)¹H NMR (400 MHz, CDCl₃) δ8.11 (br d, J=6.1 Hz, 1H), 7.55 (d, J=5.8 Hz, 1H), 7.28-7.22 (m, 3H),7.08 (br s, 2H), 7.01 (d, J=8.6 Hz, 2H), 6.79 (d, J=8.6 Hz, 2H), 5.40(br s, 1H), 5.30 (s, 1H), 4.83 (br s, 1H), 3.78 (s, 3H), 1.66 (s, 3H),1.51 (d, J=6.8 Hz, 3H), 1.04 (s, 2H); HRMS(B) m/z 419.2083 (M+H)⁺.

Example 205

To a solution of tert-butyl4-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzyl)-2,2-dimethylpiperazine-1-carboxylate(78 mg, 0.14 mmol) in DCM (1 mL) was added TFA (1 mL, 12 mmol) slowly at−78° C. The reaction was stirred at room temperature for 1 h then wasconcentrated and diluted with DCM (10 mL). The solution was stirred with3 eq. of MP-carbonate resin (3.28 mmol/g, Biotage) for 1 h at roomtemperature. The resin was removed by filtration and washed (2×5 mL)with DCM. The filtrate was concentrated and purified through HPLC togive(S)-3-(2-(((S)-1-(4-((3,3-dimethylpiperazin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneas a white solid (23 mg, 36% yield).

¹H NMR (400 MHz, MeOD) δ 8.07 (d, J=5.8 Hz, 1H), 7.30 (d, J=5.8 Hz, 1H),7.26-7.18 (m, 4H), 5.00 (q, J=6.9 Hz, 1H), 4.62 (br s, 1H), 4.36-4.16(m, 2H), 3.36 (s, 2H), 2.81 (br t, J=5.1 Hz, 2H), 2.30 (br s, 2H), 2.10(br s, 2H), 1.82 (br s, 1H), 1.45 (d, J=7.0 Hz, 3H), 1.08 (s, 6H), 0.67(br s, 3H), 0.52 (br s, 3H); HRMS(B) m/z 453.2969 (M+H)+.

Example 206

A mixture of benzyl4-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzyl)piperazine-1-carboxylate(190 mg, 0.34 mmol) and 10% Pd—C(40 mg, 0.038 mmol) in ethanol (3.4 ml)is stirred under 1 atmosphere pressure of hydrogen for 3 h. The mixtureis filtered and concentrated to give(S)-4-isopropyl-3-(2-(((S)-1-(4-(piperazin-1-ylmethyl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneas a white solid (97 mg, 67.2% yield).

¹H NMR (400 MHz, MeOD) δ 8.08 (d, J=5.8 Hz, 1H), 7.30 (d, J=5.8 Hz, 1H),7.28-7.19 (m, 4H), 5.01 (q, J=7.0 Hz, 1H), 4.63 (br s, 1H), 4.37-4.14(m, 2H), 3.44 (s, 2H), 2.78 (t, J=5.0 Hz, 4H), 2.39 (br s, 4H), 1.89 (brs, 1H), 1.45 (d, J=7.0 Hz, 3H), 0.68 (br s, 3H), 0.52 (br s, 3H);HRMS(B) m/z 425.2662 (M+H)+.

Example 207

In a 5 mL microwave vial a solution of(S)-3-(2-((S)-1-(4-bromophenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one(86 mg, 0.21 mmol), pyridin-4-ylboronic acid (26 mg, 0.21 mmol), Sodiumbicarbonate (0.21 mL, 0.42 mmol, 2 M solution) in Dioxane (1 mL) wasbubbled N2 for 3 min then Cl2Pd(dppf).CH₂Cl₂ (17 mg, 0.021 mmol) wasadded. The capped tube was heated to 100° C. for 16 h. After cooling thereaction mixture was diluted with EtOAc (10 mL) and washed with water(10 mL). After separation, the aqueous phase was extracted with EtOAc(3×10 mL). Combined organics were dried over Na₂SO₄, filtered andconcentrated. The crude material was purified through silica gel columnchromatography (EtOAc in Heptane 12 to 100%) to yield(S)-4-isopropy-3-(2-(((S)-1-(4-(2-yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneas a white solid (27 mg, 30.5% yield).

¹H NMR (400 MHz, MeOD) δ 8.35 (d, J=5.4 Hz, 1H), 8.08 (d, J=5.9 Hz, 1H),7.64-7.60 (m, 2H), 7.49 (br d, J=1.8 Hz, 1H), 7.43-7.39 (m, 3H), 7.30(d, J=5.8 Hz, 1H), 5.02 (q, J=6.8 Hz, 1H), 4.55 (br s, 1H), 4.27-4.18(m, 2H), 2.52 (s, 3H), 1.65 (br s, 1H), 1.49 (d, J=7.1 Hz, 3H), 0.55 (brs, 3H), 0.43 (br s, 3H); HRMS(B) m/z 418.2227 (M+H)+.

Example 208

To a solution of tert-butyl4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl((S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)carbamate(45 mg, 0.09 mmol) in DCM (1 mL) was added TFA (1 mL, 12 mmol) slowly at−78° C. The reaction was stirred at room temperature for 1 h then wasconcentrated and diluted with DCM (10 mL). The solution was washed withsaturated NaHCO₃ solution and brine. After separation, the aqueous phasewas extracted with DCM (3×10 mL). Combined organics were dried overNa₂SO₄, filtered and concentrated to give(S)-4-isopropyl-3-(2-(((S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneas a white solid (35 mg, 97% yield).

¹H NMR (400 MHz, MeOD) δ 8.09 (d, J=5.9 Hz, 1H), 7.86 (s, 1H), 7.72 (d,J=0.8 Hz, 1H), 7.45-7.41 (m, 2H), 7.30 (d, J=5.8 Hz, 1H), 7.25 (d, J=7.9Hz, 2H), 4.97 (q, J=7.0 Hz, 1H), 4.58 (br s, 1H), 4.30-4.21 (m, 2H),3.86 (s, 3H), 1.66 (br s, 1H), 1.48 (d, J=7.0 Hz, 3H), 0.60 (br s, 3H),0.48 (br s, 3H); HRMS(B) m/z 407.2179 (M+H)+.

Example 209

Following the above procedure for Example 208,N-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)phenyl)cyclohexanecarboxamidewas prepared as a white solid (45 mg, 92% yield) from tert-butyl(S)-1-(4-(cyclohexanecarboxamido)phenyl)ethyl(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)carbamate.

¹H NMR (400 MHz, MeOD) δ 8.08 (d, J=5.9 Hz, 1H), 7.47-7.41 (m, 2H), 7.30(d, J=5.8 Hz, 1H), 7.23-7.16 (m, 2H), 4.95 (q, J=7.0 Hz, 1H), 4.60 (brs, 1H), 4.32-4.19 (m, 2H), 2.30 (tt, J=11.8, 3.3 Hz, 1H), 1.89-1.72 (m,4H), 1.72-1.63 (m, 1H), 1.54-1.39 (m, 5H), 1.39-1.14 (m, 4H), 0.67 (brs, 3H), 0.54 (br s, 3H); HRMS(B) m/z 452.2636 (M+H)+.

Example 210

A solution of4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzaldehyde(35 mg, 0.1 mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (14 mg,0.11 mmol) in MeOH (2 mL) was added acetic acid (7.2 mg, 0.12 mmol) and5-Ethyl-2-methylpyridine borane complex (14 mg, 0.1 mmol, sigmaaldrich).The solution was stirred at 50° C. for 4 h then 5 drops of water wasadded. The solution was stirred at room temperature for another 2 h thendiluted with EtOAc (10 mL) and washed with water (10 mL). Afterseparation, the aqueous phase was extracted with EtOAc (3×10 mL).Combined organics were dried over Na₂SO₄, filtered and concentrated. Thecrude material was purified through HPLC to give(4S)-4-isopropyl-3-(2-(((1)-1-(4-((5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneas a white solid (10 mg, 21.7% yield).

¹H NMR (400 MHz, MeOD) δ 8.07 (d, J=5.8 Hz, 1H), 7.29 (d, J=5.8 Hz, 1H),7.25-7.20 (m, 4H), 5.00 (q, J=7.0 Hz, 1H), 4.63 (br s, 1H), 4.31-4.23(m, 2H), 3.55-3.48 (m, 2H), 2.68 (dh, J=13.6, 4.3, 3.7 Hz, 2H),2.64-2.48 (m, 4H), 2.36-2.29 (m, 4H), 2.28 (s, 4H), 1.84 (br s, 1H),1.45 (d, J=7.0 Hz, 3H), 0.68 (br s, 3H), 0.52 (br s, 3H); HRMS(B) m/z465.2975 (M+H)+.

Example 211

A solution of 3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (89.1 mg, 0.487mmol), 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (115.9 mg,0.518 mmol, 1.06 equiv), and DIPEA (0.20 mL, 1.1 mmol, 2.4 equiv) inDMSO (1.5 mL) was heated at 110° C. for 100 min. The reaction mixturewas diluted with EtOAc (8 mL) and washed with water (30 mL). Afterseparation, the aqueous phase was extracted with EtOAc (3×8 mL).Combined organics were dried over Na₂SO₄, filtered and concentrated.Silica gel column chromatography (MeOH in CH₂Cl₂ 0 to 5%) provided3-(2-(1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one(18.2 mg, white solid) in 10.3% yield.

¹H NMR (400 MHz, DMSO-d₆) 8.21 (br s, 1H), 8.00-7.97 (m, 2H), 7.65-7.61(m, 2H), 7.30 (br s, 1H), 5.28 (br s, 1H), 4.44-4.38 (br m, 2H),4.14-4.08 (m, 1H), 3.99 (br s, 0.5H), 3.75 (br s, 0.5H), 1.64 (d, J=7.0Hz, 3H); HRMS(B) m/z 387.0962 (M+H)⁺

Example 212

A solution of (S)-1-(4-phenoxyphenyl)ethanamine hydrochloride (281 mg,1.125 mmol), 3-(2-chloro-5-fluoropyrimidin-4-yl)oxazolidin-2-one (103mg, 0.379 mmol) and DIPEA (0.331 ml, 1.896 mmol) in DMSO was heated to110° C. for 1 h. LCMS showed little product. Heated for an additional 16h. LCMS still showed starting material. Added an additional 5equivalents of DIPEA and 1 equivalent of KF. Heated to 110° C. for 2 h.LCMS shows product. The reaction mixture was diluted with EtOAc (8 mL)and washed with water (30 mL). After separation, the aqueous phase wasextracted with EtOAc (3×8 mL). Combined organics were dried over Na₂SO₄,filtered and concentrated. Purified by column chromatography (10% to 50%EtOAc/Heptane) to give (S)-1-(5-fluoro-2-(1-(4-phenoxyphenyl)ethylamino)pyrimidin-4-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one (62 mg, 0.138 mmol).

¹H NMR (400 MHz, MeOD) δ 8.25 (d, J=2.8 Hz, 1H), 7.34 (ddd, J=8.7, 4.9,2.3 Hz, 4H), 7.16-7.04 (m, 1H), 7.02-6.90 (m, 4H), 4.96 (q, J=7.0 Hz,1H), 4.30-4.25 (m, 2H), 2.38 (dt, J=13.1, 8.4 Hz, 1H), 2.02 (br s, 1H),1.80 (ddd, J=12.7, 7.3, 4.2 Hz, 1H), 1.71-1.63 (br m, 2H), 1.61-1.49 (m,3H), 1.53 (d, J=7.0 Hz, 3H). HRMS(B) (M+H) 449.1984 Calc'd (M+H)449.1989

The compounds in Table 7 were prepared using methods substantiallysimilar to those described for the preparation of Examples 1, 113, 211and 212.

TABLE 7

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

TABLE 8 Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 7. ¹H NMR (400 MHz, CD₃OD) δ ppm Example: Name(other solvents described) LCMS 213: (S)-3-(2- 8.08 (d, J = 5.8 Hz, 1H), 7.33 (d, J = 5.8 HRMS(B) ((cyclohexylmethyl)amino) Hz, 1 H),4.80-4.76 (m, 1 H), 4.42-4.37 m/z pyrimidin-4-yl)-4- (m, 2 H), 3.24 (dd,J = 13, 6.3 Hz, 1 H), 319.2132 isopropyloxazolidin-2-one 3.10 (dt, J =13, 6.8 Hz, 1 H), 2.68-2.60 (M + H)+ (m, 1 H), 1.82-1.56 (m, 7 H),1.31-1.18 (m, 4 H), 0.98 (d, J = 7.1 Hz, 3 H), 0.87 (d, J = 7.0 Hz, 3H); 214: (R)-3-(2-(((S)-1-(4- 8.46 (d, J = 5.8 Hz, 1H), 7.85-7.73 (m,HRMS(B) bromophenyl)ethyl)amino) 5H), 7.73-7.67 (m, 1H), 7.64 (dd, J =7.1, m/z pyrimidin-4-yl)-4- 1.8 Hz, 2H), 7.58-7.52 (m, 2H), 5.92 (dd,439.0762 phenyloxazolidin-2-one J = 8.6, 4.0 Hz, 1H), 5.13 (t, J = 8.7Hz, M⁺ 1H), 4.98 (d, J = 7.0 Hz, 1H), 4.55 (dd, J = 8.7, 4.0 Hz, 1H),1.58 (d, J = 7.0 Hz, 3H); 215: (S)-3-(2-(((S)-1-(4- 8.38 (s, 1H), 8.07(d, J = 5.9 Hz, 1H), 7.30 HRMS(B) ((5,6-dihydro- (d, J = 6.0 Hz, 1H),7.28 (s, 4H), 5.03 (q, J = m/z [1,2,4]triazolo[4,3- 7.0 Hz, 1H), 4.63(br s, 1H), 4.31-4.23 463.2567 a]pyrazin-7(8H)- (m, 2H), 4.08 (t, J =5.5 Hz, 2H), 3.78- (M + H)+ yl)methyl)phenyl)ethyl)ami- 3.69 (m, 4H),2.89 (td, J = 5.4, 2.1 Hz, 2H), no)pyrimidin-4-yl)-4- 1.80 (br s, 1H),1.46 (d, J = 7.0 Hz, 3H), isopropyloxazolidin-2-one 0.68 (br s, 3H),0.53 (br s, 3H) 216: (S)-3-(2-(((S)-1-(3- 8.04 (d, J = 5.9 Hz, 1H),7.36-7.15 (m, HRMS(B) fluoro-4-((3,3,4- 2H), 7.02 (dd, J = 7.9, 1.8 Hz,1H), 6.94 m/z trimethylpiperazin-1- (dd, J = 11.0, 1.8 Hz, 1H), 4.95 (q,J = 7.0 485.3107 yl)methyl)phenyl)ethyl)ami- Hz, 1H), 4.58 (br s, 1H),4.32-4.11 (m, (M + H)+ no)pyrimidin-4-yl)-4- 2H), 3.38 (br s, 2H), 2.46(br t, J = 4.9 Hz, isopropyloxazolidin-2-one 2H), 2.32 (br s, 2H), 2.14(br s, 2 H), 2.10 (s, 3H), 1.73 (br s, 1H), 1.40 (d, J = 7.1 Hz, 3H),0.95 (s, 3H), 0.95 (s, 3H), 0.63 (br s, 3H), 0.49 (br s, 3H) 217:(S)-3-(2-(((S)-1-(3- 8.09 (d, J = 6.0 Hz, 1H), 7.41-7.20 (m, HRMS(B)fluoro-4-((4- 2H), 7.11 (dd, J = 7.8, 1.7 Hz, 1H), 7.04 m/zmethylpiperazin-1- (dd, J = 11.0, 1.8 Hz, 1H), 5.01 (q, J = 7.0 457.2699yl)methyl)phenyl)ethyl)ami- Hz, 1H), 4.63 (br s, 1H), 4.36-4.16 (m, (M +H)+. no)pyrimidin-4-yl)-4- 2H), 3.57 (s, 2H), 2.82 (br s, 4H), 2.60 (brisopropyloxazolidin-2-one s, 4H), 2.51 (s, 3H), 1.83 (br s, 1H), 1.45(d, J = 7.1 Hz, 3H), 0.69 (s, 3H), 0.54 (s, 3H) 218:(4S)-3-(2-(((1S)-1-(4- 8.07 (d, J = 5.8 Hz, 1H), 7.30 (d, J = 5.8HRMS(B) ((3,5-dimethylpiperazin-1- Hz, 1H), 7.28-7.19 (m, 4H), 5.01 (q,J = m/z yl)methyl)phenyl)ethyl)ami- 7.0 Hz, 1H), 4.63 (br s, 1H),4.34-4.18 453.2971 no)pyrimidin-4-yl)-4- (m, 2H), 3.46-3.39 (m, 2H),2.89-2.76 (M + H)+ isopropyloxazolidin-2-one (m, 2H), 2.76-2.67 (m, 2H),1.82 (br s, 1H), 1.59 (t, J = 10.9 Hz, 2H), 1.45 (d, J = 7.0 Hz, 3H),0.98 (s, 3H), 0.96 (s, 3H), 0.68 (br s, 3H), 0.52 (br s, 3H) 219:(S)-4-isopropyl-3-(2- 8.07 (d, J = 5.8 Hz, 1H), 7.30 (d, J = 5.9 HRMS(B)(((S)-1-(4-((4-methyl-1,4- Hz, 1H), 7.28-7.24 (m, 4H), 5.02 (q, J = m/zdiazepan-1- 7.0 Hz, 1H), 4.63 (br s, 1H), 4.35-4.22 453.2968yl)methyl)phenyl)ethyl)ami- (m, 2H), 3.67-3.59 (m, 2H), 3.09-3.07 (M +H)+ no)pyrimidin-4- (m, 2H), 2.99 (dd, J = 6.2, 3.5 Hz, 2H),yl)oxazolidin-2-one 2.79-2.77 (m, 2H), 2.72 (t, J = 6.0 Hz, 2H), 2.63(s, 3H), 1.93-1.87 (m, 3H), 1.80 (br s, 1H), 1.45 (d, J = 7.0 Hz, 3H),0.69 (br s, 3H), 0.54 (br s, 3H) 220: (S)-3-(2-(((S)-1-(4- 8.07 (d, J =5.9 Hz, 1H), 7.30 (d, J = 5.8 HRMS(B) ((4-(tert-butyl)piperazin-1- Hz,1H), 7.24 (q, J = 8.2 Hz, 4H), 5.01 (q, J = m/zyl)methyl)phenyl)ethyl)ami- 6.9 Hz, 1H), 4.63 (br s, 1H), 4.31-4.24481.3283 no)pyrimidin-4-yl)-4- (m, 2H), 3.49-3.42 (m, 2H), 2.60 (br s,(M + H)+ isopropyloxazolidin-2-one 4H), 2.46 (br s, 4H), 1.76 (br s,1H), 1.45 (d, J = 7.0 Hz, 3H), 1.03 (s, 9H), 0.69 (s, 3H), 0.53 (s, 3H)221: (S)-4-isopropyl-3-(2- 8.08 (d, J = 5.8 Hz, 1H), 7.30 (d, J = 5.8HRMS(B) (((S)-1-(4-((3,3,4- Hz, 1H), 7.26-7.18 (m, 4H), 5.01 (q, J = m/ztrimethylpiperazin-1- 7.0 Hz, 1H), 4.63 (br s, 1H), 4.31-4.24 467.3127yl)methyl)phenyl)ethyl)ami- (m, 2H), 3.37 (s, 2H), 2.54 (br t, J = 5.0Hz, (M + H)+ no)pyrimidin-4- 2H), 2.38 (br s, 2H), 2.17 (s, 3H), 2.14(br s, yl)oxazolidin-2-one 2H), 1.85 (br s, 1H), 1.45 (d, J = 7.0 Hz,3H), 1.01 (s, 6H), 0.68 (br s, 3H), 0.53 (br s, 3H) 222:(S)-4-isopropyl-3-(2- 8.07 (d, J = 5.8 Hz, 1H), 7.30 (d, J = 5.8 HRMS(B)(((S)-1-(4-((4- Hz, 1H), 7.24 (q, J = 8.3 Hz, 4H), 5.01 (q, J = m/zisopropylpiperazin-1- 7.0 Hz, 1H), 4.63 (br s, 1H), 4.31-4.24 467.3120yl)methyl)phenyl)ethyl)ami- (m, 2H), 3.46 (s, 2H), 2.63-2.44 (m, 9H),(M + H)+ no)pyrimidin-4- 1.84 (br s, 1H), 1.45 (d, J = 7.1 Hz, 3H),yl)oxazolidin-2-one 1.02 (d, J = 6.5 Hz, 6H), 0.68 (br s, 3H), 0.53 (brs, 3H) 223: (4S)-3-(2-(((1S)-1-(4- 8.07 (d, J = 5.9 Hz, 1H), 7.30 (d, J= 5.8 HRMS(B) ((3,4-dimethylpiperazin-1- Hz, 1H), 7.23 (q, J = 8.1 Hz,4H), 5.01 (q, J = m/z yl)methyl)phenyl)ethyl)ami- 7.0 Hz, 1H), 4.63 (brs, 1H), 4.35-4.20 453.2960 no)pyrimidin-4-yl)-4- (m, 2H), 3.51-3.35 (m,2H), 2.82-2.61 (M + H)+ isopropyloxazolidin-2-one (m, 3H), 2.36-2.24 (m,1H), 2.23 (s, 3H), 2.20-2.08 (m, 2H), 1.89-1.80 (m, 2H), 1.45 (d, J =7.0 Hz, 3H), 0.99 (d, J = 6.3 Hz, 3H), 0.68 (br s, 3H), 0.52 (br s, 3H)224: (S)-3-(2-(((S)-1-(4- 8.08 (d, J = 5.8 Hz, 1H), 7.31 (d, J = 5.8HRMS(B) ((4,4-difluoropiperidin-1- Hz, 1H), 7.25 (q, J = 8.2 Hz, 4H),5.02 (q, J = m/z yl)methyl)phenyl)ethyl)ami- 7.0 Hz, 1H), 4.63 (br s,1H), 4.32-4.24 460.2514 no)pyrimidin-4-yl)-4- (m, 2H), 3.51 (s, 2H),2.52 (br t, J = 5.8 Hz, (M + H)+ isopropyloxazolidin-2-one 4H),1.98-1.87 (m, 4H), 1.81 (br s, 1H), 1.46 (d, J = 7.0 Hz, 3H), 0.68 (brs, 3H), 0.52 (br s, 3H) 225: 2-fluoro-4-((S)-1-((4- 8.09 (d, J = 5.7 Hz,1H), 7.58 (t, J = 7.7 Hz, HRMS(B) ((S)-4-isopropyl-2- 1H), 7.33 (d, J =5.8 Hz, 1H), 7.20 (dd, J = m/z oxooxazolidin-3- 7.9, 1.6 Hz, 1H), 7.13(dd, J = 12.1, 1.7 Hz, 568.2549 yl)pyrimidin-2- 1H), 5.03 (q, J = 7.0Hz, 1H), 4.61 (br s, (M + H)+ yl)amino)ethyl)-N-(4- 1H), 4.31-4.24 (m,2H), 3.97-3.80 (m, (2,2,2- 3H), 3.65 (dt, J = 4.7, 2.3 Hz, 1H), 1.90(dt, trifluoroethoxy)cyclohexyl) J = 12.5, 4.0 Hz, 2H), 1.72-1.58 (m,6H), benzamide 1.47 (d, J = 7.0 Hz, 3H), 0.68 (br s, 3H), 0.56 (br s,3H) 226: 2-fluoro-N-(4- 8.09 (d, J = 6.0 Hz, 1H), 7.58 (t, J = 7.7 Hz,HRMS(B) hydroxy-4- 1H), 7.33 (d, J = 5.8 Hz, 1H), 7.20 (dd, J = m/zmethylcyclohexyl)-4-((S)- 8.0, 1.6 Hz, 1H), 7.13 (dd, J = 12.0, 1.7 Hz,500.2589 1-((4-((S)-4-isopropyl-2- 1H), 5.03 (q, J = 7.0 Hz, 1H), 4.61(br s, (M + H)+ oxooxazolidin-3- 1H), 4.31-4.25 (m, 2H), 3.89 (dt, J =9.4, yl)pyrimidin-2- 4.7 Hz, 1H), 1.95-1.82 (m, 2H), 1.75-yl)amino)ethyl)benzamide 1.49 (m, 7H), 1.47 (d, J = 7.0 Hz, 3H), 1.21(s, 3H), 0.68 (br s, 3H), 0.56 (br s, 3H) 227: (4S)-3-(2-(((1S)-1-(3-8.09 (d, J = 5.8 Hz, 1H), 7.32 (d, J = 5.8 HRMS(B) fluoro-4- Hz, 1H),7.29 (t, J = 7.7 Hz, 1H), 7.10 (dd, m/z ((hexahydropyrrolo[1,2- J = 7.9,1.8 Hz, 1H), 7.03 (dd, J = 11.0, 1.8 483.2878 a]pyrazin-2(1H)- Hz, 1H),5.00 (q, J = 7.0 Hz, 1H), 4.63 (br (M + H)+ yl)methyl)phenyl)ethyl)ami-s, 1H), 4.31-4.24 (m, 2H), 3.62-3.53 (m, no)pyrimidin-4-yl)-4- 2H),2.98-2.91 (m, 3H), 2.80-2.75 (m, isopropyloxazolidin-2-one 1H),2.34-2.18 (m, 2H), 2.18-2.01 (m, 2H), 1.90 (t, J = 10.4 Hz, 1H),1.83-1.65 (m, 4H), 1.45 (d, J = 7.0 Hz, 3H), 1.36- 1.27 (m, 1H), 0.68(br s, 3H), 0.54 (br s, 3H) 228: (S)-3-(2-((S)-1-(4-((4- 8.07 (d, J =5.9 Hz, 1H), 7.30 (d, J = 5.8 HRMS(B) cyclopropylpiperazin-1- Hz, 1H),7.23 (q, J = 8.0 Hz, 4H), 5.01 (q, J = m/z yl)methyl)phenyl)ethylami-7.0 Hz, 1H), 4.62 (br s, 1H), 4.35-4.19 465.2975 no)pyrimidin-4-yl)-4-(m, 2H), 3.45 (s, 2H), 2.62 (br s, 4H), 2.41 (M + H)+isopropyloxazolidin-2-one (br s, 4H), 1.79 (br s, 1H), 1.65-1.56 (m,1H), 1.45 (d, J = 7.0 Hz, 3H), 0.67 (br s, 3H), 0.52 (br s, 3H),0.45-0.38 (m, 2H), 0.38-0.29 (m, 2H) 229: (S)-3-(2-((S)-1-(4-((4- 8.08(d, J = 7.2 Hz, 1H), 7.70 (d, J = 7.2 HRMS(B) cyclobutylpiperazin-1- Hz,1H), 7.47-7.24 (m, 4H), 5.28-5.06 m/z yl)methyl)phenyl)ethylami- (m,1H), 4.66 (q, J = 4.8, 4.4 Hz, 1H), 4.34 479.3165 no)pyrimidin-4-yl)-4-(d, J = 5.7 Hz, 2H), 3.91 (s, 2H), 3.61 (p, J = (M + H)+isopropyloxazolidin-2-one 8.3 Hz, 1H), 3.20 (br s, 4H), 3.02 (br s, 4H),2.32-2.04 (m, 4H), 1.90-1.66 (m, 3H), 1.52 (d, J = 7.0 Hz, 3H), 0.71 (d,J = 7.0 Hz, 3H), 0.54 (d, J = 6.7 Hz, 3H) 230: (4S)-3-(2-((1S)-1-(4-8.07 (d, J = 5.8 Hz, 1H), 7.34-7.19 (m, HRMS(B) ((dihydro-1H-pyrido[1,2-5H), 5.01 (q, J = 7.0 Hz, 1H), 4.63 (br s, m/z a]pyrazin- 1H), 4.33-4.22(m, 2H), 3.49-3.39 (m, 479.3131 2(6H,7H,8H,9H,9aH)- 2H), 2.83-2.71 (m,2H), 2.66 (dq, J = (M + H)+ yl)methyl)phenyl)ethylami- 11.0, 2.2 Hz,2H), 2.32-2.14 (m, 2H), no)pyrimidin-4-yl)-4- 2.09-1.94 (m, 2H), 1.82(t, J = 10.8 Hz, isopropyloxazolidin-2-one 1H), 1.70 (dt, J = 12.4, 3.5Hz, 1H), 1.64- 1.50 (m, 2H), 1.48-1.39 (m, 5H), 1.35- 1.21 (m, 1H), 1.14(tdd, J = 13.0, 10.8, 3.6 Hz, 1H), 0.68 (br s, 3H), 0.52 (br s, 3H) 231:(4S)-4-isopropyl-3-(2- 8.07 (d, J = 5.9 Hz, 1H), 7.36-7.21 (m, HRMS(B)((1S)-1-(4-((3-methyl-3,8- 5H), 5.01 (q, J = 7.0 Hz, 1H), 4.62 (br s,m/z diazabicyclo[3.2.1]octan- 1H), 4.33-4.21 (m, 2H), 3.45 (s, 2H), 3.07465.2964 8- (qd, J = 4.6, 4.2, 1.9 Hz, 2H), 2.63-2.50 (M + H)+yl)methyl)phenyl)ethylami- (m, 2H), 2.25 (ddd, J = 10.7, 4.4, 1.8 Hz,no)pyrimidin-4- 2H), 2.15 (s, 3H), 2.04-1.93 (m, 2H), 1.83-yl)oxazolidin-2-one 1.72 (m, 3H), 1.45 (d, J = 7.0 Hz, 3H), 0.67 (br s,3H), 0.51 (br s, 3H) 232: (4S)-4-isopropyl-3-(2- (CDCl₃) 8.17 (d, J =5.7 Hz, 1H), 7.42 (d, J = HRMS(B) ((1S)-1-(4-((8-methyl-3,8- 5.7 Hz,1H), 7.23 (s, 4H), 5.46 (br s, 1H), m/z diazabicyclo[3.2.1]octan- 5.01(br s, 1H), 4.60 (dt, J = 6.9, 3.3 Hz, 465.2963 3- 1H), 4.28 (t, J = 8.7Hz, 1H), 4.21 (dd, J = (M + H)+ yl)methyl)phenyl)ethylami- 9.1, 3.1 Hz,1H), 3.42 (d, J = 1.7 Hz, 2H), no)pyrimidin-4- 3.10-2.96 (m, 2H),2.58-2.48 (m, 2H), yl)oxazolidin-2-one 2.33-2.18 (m, 5H), 2.06-1.84 (m,3H), 1.81 (dd, J = 7.8, 4.4 Hz, 2H), 1.52 (d, J = 6.8 Hz, 3H), 0.71 (brs, 3H), 0.64 (br s, 3H) 233: (4S)-3-(2-((1S)-1-(4- 8.12 (d, J = 5.8 Hz,1H), 7.34 (d, J = 5.8 HRMS(B) ((hexahydropyrrolo[1,2- Hz, 1H), 7.33-7.24(m, 4H), 5.05 (q, J = m/z a]pyrazin-2(1H)- 7.0 Hz, 1H), 4.67 (br s, 1H),4.38-4.26 465.2972 yl)methyl)phenyl)ethylami- (m, 2H), 3.64-3.49 (m,2H), 3.11-3.00 (M + H)+ no)pyrimidin-4-yl)-4- (m, 2H), 2.96 (br d, J =11.0 Hz, 1H), 2.83 isopropyloxazolidin-2-one (br d, J = 11.2 Hz, 1H),2.45-2.34 (m, 1H), 2.32-2.25 (m, 3H), 1.94 (t, J = 10.5 Hz, 1H),1.88-1.77 (m, 4H), 1.49 (d, J = 7.0 Hz, 3H), 1.47-1.35 (m, 1H), 0.72 br(s, 3H), 0.56 (br s, 3H) 234: (S)-3-(2-(((S)-1-(2H- HRMS(B)tetrazol-5-yl) ethyl) amino) m/z pyrimidin-4-yl)-4- 319.1624isopropyloxazolidin-2-one (M + H )+, RT = 1.33 min. 235: benzyl4-(4-((S)-1-(4- 8.07 (d, J = 5.8 Hz, 1H), 7.34-7.18 (m, HRMS(B)((S)-4-isopropyl-2- 10H), 5.05 (s, 2H), 5.01 (q, J = 6.9 Hz, m/zoxooxazolidin-3- 1H), 4.62 (br s, 1H), 4.32-4.18 (m, 2H), 559.3026yl)pyrimidin-2- 3.49-3.34 (m, 4H), 3.46 (s, 2H), 2.36 (t, J = (M + H)+ylamino)ethyl)benzyl)piper- 5.1 Hz, 4H), 1.75 (br s, 1H), 1.45 (d, J =azine-1-carboxylate 7.0 Hz, 3H), 0.66 (br s, 3H), 0.50 (br s, 3H) 236:(S)-3-(2-((S)-1-(4-((4- 8.07 (d, J = 5.8 Hz, 1H), 7.30 (d, J = 5.8HRMS(B) amino-4-methylpiperidin- Hz, 1H), 7.27-7.21 (m, 4H), 5.01 (q, J= m/z 1- 7.0 Hz, 1H), 4.63 (br s, 1H), 4.34-4.18 453.2972yl)methyl)phenyl)ethylami- (m, 2H), 3.53-3.40 (m, 2H), 2.59-2.21 (M +H)+ no)pyrimidin-4-yl)-4- (br m, 4H), 1.78 (br s, 1H), 1.52 (ddt, J =isopropyloxazolidin-2-one 11.8, 8.7, 5.2 Hz, 4H), 1.45 (d, J = 7.0 Hz,3H), 1.07 (s, 3H), 0.67 (br s, 3H), 0.51 (br s, 3H) 237:(S)-3-(2-((S)-1-(4-((4- (CDCl₃) 8.17 (d, J = 5.7 Hz, 1H), 7.42 (d, J =HRMS(B) (dimethylamino)piperidin- 5.7 Hz, 1H), 7.25 (d, J = 8.2 Hz, 4H),m/z 1- 5.43 (br s, 1H), 5.01 (br s, 1H), 4.60 (dt, J = 467.3121yl)methyl)phenyl)ethylami- 8.6, 3.3 Hz, 1H), 4.28 (t, J = 8.7 Hz, 1H),(M + H)+ no)pyrimidin-4-yl)-4- 4.21 (dd, J = 9.1, 3.2 Hz, 1H), 3.44 (s,2H), isopropyloxazolidin-2-one 2.89 (dp, J = 11.5, 2.8 Hz, 2H), 2.26 (s,6H), 2.11 (tt, J = 11.3, 3.6 Hz, 1H), 1.93 (td, J = 11.9, 2.4 Hz, 2H),1.90 (br s, 1H), 1.75 (dq, J = 12.0, 2.8 Hz, 2H), 1.60-1.43 (m, 2H),1.53 (d, J = 6.8 Hz, 3H), 0.70 (br s, 3H), 0.63 (br s, 3H) 238:(S)-3-(2-((S)-1-(4- (CDCl₃) δ 8.18 (dd, J = 5.8, 1.3 Hz, 1H), HRMS(B)((tert- 7.44 (dd, J = 5.7, 1.2 Hz, 1H), 7.37-7.22 m/zbutylamino)methyl)phenyl) (m, 5H), 5.52 (br s, 1H), 5.15-4.95 (m,412.2701 ethylamino)pyrimidin-4-yl)- 1H), 4.70-4.55 (m, 1H), 4.30 (td, J= 8.8, (M + H)+ 4-isopropyloxazolidin-2- 2.1 Hz, 1H), 4.23 (dd, J = 9.1,3.0 Hz, 1H), one 3.71 (d, J = 2.0 Hz, 2H), 2.06 (s, 1H), 1.54 (dd, J =7.1, 1.9 Hz, 3H), 1.18 (sm, 9H), 0.85-0.59 (m, 6H); 239:N-tert-butyl-4-((S)-1- (CDCl₃) δ 8.16 (dd, J = 5.8, 1.2 Hz, 1H), HRMS(B)(4-((S)-4-isopropyl-2- 7.66 (d, J = 8.3 Hz, 2H), 7.43 (dd, J = 5.8, m/zoxooxazolidin-3- 0.9 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 5.88 426.2488yl)pyrimidin-2- (s, 1H), 5.57 (br s, 1H), 5.04 (br s, 1H), (M + H)+ylamino)ethyl)benzamide 4.55 (br s, 1H), 4.26 (t, J = 8.7 Hz, 1H), 4.19(dd, J = 9.2, 3.2 Hz, 1H), 1.53 (d, J = 6.9 Hz, 3H), 1.45 (s, 9H), 0.64(m, 6H) 240: N-cyclohexyl-4-((S)- (CDCl₃) δ 8.17 (d, J = 5.7 Hz, 1H),7.69 (d, HRMS(B) 1-(4-((S)-4-isopropyl-2- J = 8.1 Hz, 2H), 7.44 (d, J =5.8 Hz, 1H), m/z oxooxazolidin-3- 7.36 (d, J = 7.9 Hz, 2H), 5.91 (d, J =8.3 452.2640 yl)pyrimidin-2- Hz, 1H), 5.51 (br s, 1H), 5.04 (br s, 1H),(M + H)+ ylamino)ethyl)benzamide 4.53 (br s, 1H), 4.26 (t, J = 8.7 Hz,1H), 4.19 (dd, J = 9.1, 3.2 Hz, 1H), 4.04-3.89 (m, 1H), 2.07-1.95 (m,2H), 1.74 (dp, J = 11.5, 3.8 Hz, 2H), 1.64 (tt, J = 7.4, 3.7 Hz, 2H),1.54 (d, J = 6.9 Hz, 3H), 1.42 (qt, J = 12.4, 3.5 Hz, 2H), 1.30-1.17 (m,3H), 0.64 (br s, 6H) 241: 4-((S)-1-(4-((S)-4- (CDCl₃) δ 8.19 (d, J = 5.8Hz, 1H), 7.83 (d, HRMS(B) isopropyl-2-oxooxazolidin- J = 8.2 Hz, 2H),7.77 (s, 1H), 7.68-7.59 m/z 3-yl)pyrimidin-2- (m, 2H), 7.48-7.41 (m,3H), 7.37 (dd, J = 446.2170 ylamino)ethyl)-N- 8.5, 7.3 Hz, 2H),7.22-7.11 (m, 1H), 5.48 (M + H)+ phenylbenzamide (br s, 1H), 5.08 (br s,1H), 4.56 (br s, 1H), 4.27 (t, J = 8.7 Hz, 1H), 4.20 (dd, J = 9.2, 3.2Hz, 1H), 1.57 (t, J = 5.6 Hz, 3H), 0.65 (br s, 6H); 242:(S)-4-isopropyl-3-(2- (CDCl₃) δ 8.18 (d, J = 5.7 Hz, 1H), 7.45 (d,HRMS(B) ((S)-1-(4-(piperidine-1- J = 5.7 Hz, 1H), 7.33 (s, 4H), 5.45 (brs, m/z carbonyl)phenyl)ethylami- 1H), 5.05 (br s, 1H), 4.59 (dt, J =7.3, 2.9 438.2492 no)pyrimidin-4- Hz, 1H), 4.27 (t, J = 8.7 Hz, 1H),4.21 (dd, (M + H)+ yl)oxazolidin-2-one J = 9.1, 3.2 Hz, 1H), 3.51 (d, J= 141.8 Hz, 4H), 1.60 (dd, J = 52.4, 5.9 Hz, 10H), 0.68 (d, J = 25.5 Hz,6H); 243: (S)-4-isopropyl-3-(2- (CDCl₃) δ 8.18 (d, J = 5.7 Hz, 1H), 7.45(d, HRMS(B) ((S)-1-(4-(4- J = 5.7 Hz, 1H), 7.35 (s, 4H), 5.42 (br s, m/zmethylpiperazine-1- 1H), 5.05 (br s, 1H), 4.58 (br s, 1H), 4.28 453.2611carbonyl)phenyl)ethylami- (t, J = 8.8 Hz, 1H), 4.21 (dd, J = 9.2, 3.1(M + H)+ no)pyrimidin-4- Hz, 1H), 3.78 (br s, 2H), 3.44 (br s, 2H),yl)oxazolidin-2-one 2.53-2.39 (m, 2H), 2.32 (s, 4H), 1.65 (m, 2H), 1.53(d, J = 6.9 Hz, 3H), 0.82-0.50 (m, 6H) 244: (S)-4-isopropyl-3-(2-(CDCl₃) δ 8.16 (d, J = 5.7 Hz, 1H), 7.42 (d, HRMS(B)((S)-1-(4-(piperidin-1- J = 5.7 Hz, 1H), 7.24 (s, 4H), 5.58 (br s, m/zylmethyl)phenyl)ethylami- 1H), 5.15-4.85 (m, 1H), 4.60 (dt, J = 8.4,424.2704 no)pyrimidin-4- 3.4 Hz, 1H), 4.27 (t, J = 8.7 Hz, 1H), 4.20(M + H)+ yl)oxazolidin-2-one (dd, J = 9.1, 3.2 Hz, 1H), 3.43 (s, 2H),2.54- 2.22 (m, 4H), 1.99 (br s, 1H), 1.61-1.48 (m, 7H), 1.42 (q, J =6.6, 6.0 Hz, 2H), 0.86- 0.41 (m, 6H); 245: (S)-4-isopropyl-3-(2- (CDCl₃)δ 8.18 (d, J = 5.7 Hz, 1H), 7.45 (d, HRMS(B) ((S)-1-(4- J = 5.7 Hz, 1H),7.28 (s, 4H), 5.56 (br s, m/z (morpholinomethyl)phe- 1H), 5.16-4.94 (m,1H), 4.63 (dt, J = 7.6, 426.2487 nyl)ethylamino)pyrimidin-4- 3.5 Hz,1H), 4.30 (t, J = 8.8 Hz, 1H), 4.23 (M + H)+ yl)oxazolidin-2-one (dd, J= 9.0, 3.1 Hz, 1H), 3.72 (t, J = 4.6 Hz, 4H), 3.49 (s, 2H), 2.45 (t, J =4.6 Hz, 4H), 2.19-1.82 (m, 1H), 1.55 (d, J = 6.9 Hz, 3H), 0.90-0.46 (m,6H); 246: (S)-4-isopropyl-3-(2- (CDCl₃) δ 8.17 (d, J = 5.8 Hz, 1H), 7.43(d, HRMS(B) ((S)-1-(4-((4- J = 5.8 Hz, 1H), 7.27 (d, J = 6.2 Hz, 4H),m/z methylpiperazin-1- 5.52 (br s, 1H), 5.03 (br s, 0H), 4.62 (dt, J =439.2801 yl)methyl)phenyl)ethylami- 8.5, 3.4 Hz, 1H), 4.29 (t, J = 8.7Hz, 1H), (M + H)+ no)pyrimidin-4- 4.22 (dd, J = 9.1, 3.2 Hz, 1H), 3.48(s, 2H), yl)oxazolidin-2-one 2.46 (br s, 9H), 2.30 (s, 3H), 1.54 (d, J =6.9 Hz, 3H), 0.97-0.57 (m, 6H); 247: (R)-4-(4- (CDCl₃) δ 8.18 (d, J =5.8 Hz, 1 H), 7.41 (d, HRMS(B) fluorophenyl)-4-methyl-3- J = 5.8 Hz, 1H), 7.33-7.29 (m, 2 H), 7.25- m/z (2-((S)-1- 7.20 (m, 3 H), 7.15-7.06(m, 4 H), 5.17 393.1726 phenylethylamino)pyrimidin- (br s, 1 H), 4.21(br s, 1 H), 4.20-4.15 (m, (M + H)+. 4-yl)oxazolidin-2-one 2 H), 1.61(s, 3 H), 1.21 (d, J = 7.1 Hz, 3 H) 248: (S)-1-(2-(1- (CDCl₃) δ 8.19 (d,J = 5.8 Hz, 1 H), 7.37- HRMS(B) phenylethylamino)pyrimidin- 7.33 (m, 4H), 7.29-7.24 (m, 2 H), 5.39 m/z 4-yl)-3-oxa-1- (br s, 1 H), 5.12-5.05(m, 1 H), 4.09- 339.1805 azaspiro[4.4]nonan-2-one 4.05 (m, 2 H),2.83-2.75 (m, 1 H), 2.35 (M + H)+ (br s, 1 H), 1.95-1.86 (m, 1 H), 1.71(br s, 1 H), 1.67-1.61 (m, 2 H), 1.58 (d, J = 7.0 Hz, 3 H), 1.45 (br s,2 H) 249: (R)-4-(4- (CDCl₃) δ 8.18 (d, J = 5.8 Hz, 1 H), 7.42 (d,HRMS(B) fluorophenyl)-4-methyl-3- J = 5.8 Hz, 1 H), 7.38-7.33 (m, 2 H),7.26- m/z (2-((S)-1-(4- 7.22 (m, 2 H), 7.14-7.06 (m, 5 H), 7.00-485.1979 phenoxyphenyl)ethylami- 6.94 (m, 4 H), 5.21 (br s, 1 H), 4.23-(M + H)+ no)pyrimidin-4- 4.17 (m, 3 H), 1.71 (br s, 3 H), 1.20 (d, J =yl)oxazolidin-2-one 6.8 Hz, 3 H) 250: (S)-4-methyl-3-(2- (CDCl₃) δ 8.17(dd, J = 5.9, 1.1 Hz, 1H), HRMS(B) ((S)-1-(4- 7.47-7.23 (m, 8H),7.16-7.05 (m, 3H), m/z phenoxyphenyl)ethylami- 7.02-6.91 (m, 4H), 5.10(br s, 1H), 4.22 467.2065 no)pyrimidin-4-yl)-4- (s, 2H), 1.73 (s, 3H),1.67-1.53 (m, 1H), (M + H)+ phenyloxazolidin-2-one 1.14 (d, J = 7.0 Hz,3H); 251: (S)-1-(2-(1-(4- (CDCl₃) δ 8.19 (d, J = 5.8 Hz, 1 H), 7.37-HRMS(B) phenoxyphenyl)ethylami- 7.28 (m, 5 H), 7.13-7.09 (m, 1 H), 7.01-m/z no)pyrimidin-4-yl)-3-oxa-1- 6.96 (m, 4 H), 5.47 (br s, 1 H),5.12-5.05 431.2073 azaspiro[4.4]nonan-2-one (m, 1 H), 4.11-4.07 (m, 2H), 2.84-2.76 (M + H)+ (m, 1 H), 2.42 (br s, 1 H), 1.97-1.88 (m, 1 H),1.77 (br s, 1 H), 1.68-1.61 (m, 2 H), 1.58 (d, J = 6.9 Hz, 3 H),1.54-1.46 (m, 2 H) 252: (S)-4,4-dimethyl-3-(2- (CDCl₃) δ 8.19 (d, J =5.8 Hz, 1H), 7.38- MS m/z (1-(4- 7.26 (m, 5H), 7.11 (tt, J = 7.4, 1.1Hz, 1H), 405.1 phenoxyphenyl)ethylami- 7.01-6.94 (m, 4H), 5.37 (br s,1H), 5.01 (M + H)+ no)pyrimidin-4- (d, J = 9.1 Hz, 1H), 4.09-3.93 (m,2H), yl)oxazolidin-2-one 1.71 (s, 3H), 1.57 (d, J = 6.9 Hz, 3H), 1.28(m, 3H); 253: (S)-3-(2-(((S)-1-(1- 8.49 (d, J = 5.7 Hz, 1H), 7.84-7.38(m, HRMS(B) benzyl-5-methyl-1H- 7H), 5.65 (s, 1.2H), 5.55 (s, 0.8H),5.43 (M + H) pyrazol-4- (dq, J = 8.9, 6.9 Hz, 1H), 5.11 (tt, J = 6.1,421.2338 yl)ethyl)amino)pyrimidin-4- 3.6 Hz, 1H), 4.79-4.60 (m, 2H),2.76 (dtt, yl)-4-isopropyloxazolidin- J = 22.3, 7.2, 3.5 Hz, 1H), 2.56(2s, 3H), 2-one 1.87 (2d, J = 6.9 Hz, 3H), 1.22 (2d, J = 7.1 Hz, 3H),1.13 (dd, J = 6.9 Hz, 3H) 254: (S)-3-(2-(((S)-1-(1- 8.14 (d, J = 5.8 Hz,1H), 7.50 (s, 1H), 7.38 HRMS(B) benzyl-3-methyl-1H- (d, J = 5.8 Hz, 1H),7.36-7.25 (m, 3H), (M + H) pyrazol-4- 7.24-7.17 (m, 2H), 5.21 (s, 2H),5.06 (q, J = 421.2340 yl)ethyl)amino)pyrimidin-4- 6.9 Hz, 1H), 4.76 (dt,J = 7.5, 3.9 Hz, yl)-4-isopropyloxazolidin- 1H), 4.42-4.32 (m, 2H), 2.38(br s, 1H), 2-one 2.22 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H), 0.86 (d, J =7.0 Hz, 3H), 0.75 (d, J = 6.9 Hz, 3H). 255: (4S)-4-isopropyl-3-(2- ¹HNMR (400 MHz, MeOD) δ 8.16 (d, J = HRMS(B) (1-(1-methyl-1H-pyrazol-4-5.8 Hz, 0.5H), 8.14 (d, J = 5.8 Hz, 0.5H), (M + H)yl)ethylamino)pyrimidin-4- 7.54 (s, 0.5H), 7.48 (s, 0.5H), 7.44 (s,421.2340 yl)oxazolidin-2-one 0.5H), 7.40 (d, J = 2.0 Hz, 0.5H), 7.38 (d,J = 2.0 Hz, 0.5H), 7.38 (s, 0.5H), 5.11 (q, J = 6.9 Hz, 1H), 4.75 (dq, J= 9.4, 3.7 Hz, 1H), 4.46-4.29 (m, 2H), 3.85 (d, J = 5.5 Hz, 3H), 2.62(ddq, J = 10.4, 7.0, 3.5 Hz, 0.5H), 2.40 (br s, 0.5H), 1.53 (d, J = 6.9Hz, 3H), 0.98 (d, J = 7.1 Hz, 1.5H), 0.88 (d, J = 7.1 Hz, 1.5H), 0.86(d, J = 7.0 Hz, 1.5H), 0.78 (d, J = 7.0 Hz, 1.5H). HRMS(B) (M + H)421.2340 Calc'd (M + H) 421.2352 256: (S)-3-(2-((S)-1-(3- 8.20 (d, J =2.5 Hz, 1H), 8.16 (d, J = 5.8 HRMS(B) (1H-pyrazol-1- Hz, 1H), 7.75 (t, J= 2.0 Hz, 1H), 7.72 (d, J = (M + H) yl)phenyl)ethylami- 1.8 Hz, 1H),7.58 (ddd, J = 8.0, 2.2, 1.0 393.2036 no)pyrimidin-4-yl)-4- Hz, 1H),7.43 (t, J = 7.8 Hz, 1H), 7.37 (d, J = isopropyloxazolidin-2-one 5.8 Hz,1H), 7.32 (d, J = 7.6 Hz, 1H), 6.56-6.49 (m, 1H), 5.13 (q, J = 7.0 Hz,1H), 4.66 (br s, 1H), 4.39-4.19 (m, 2H), 1.82 (br s, 1H), 1.58 (d, J =7.0 Hz, 3H), 0.56 (br s, 6H). 257: (S)-3-(2-((S)-1-(4- 8.18 (d, J = 2.5Hz, 1H), 8.16 (d, J = 5.8 HRMS(B) (1H-pyrazol-1- Hz, 1H), 7.72 (d, J =1.8 Hz, 1H), 7.69 (d, J = (M + H) yl)phenyl)ethylami- 1.9 Hz, 1H), 7.67(d, J = 2.0 Hz, 1H), 393.2050 no)pyrimidin-4-yl)-4- 7.52-7.44 (m, 2H),7.37 (d, J = 5.8 Hz, isopropyloxazolidin-2-one 1H), 6.56-6.49 (m, 1H),5.11 (q, J = 7.1 Hz, 1H), 4.68 (s, 1H), 4.40-4.24 (m, 2H), 1.86 (s, 1H),1.57 (d, J = 7.1 Hz, 3H), 0.71 (s, 3H), 0.59 (s, 3H). 258:(4S)-4-isopropyl-3-(2- 8.17 (dd, J = 5.8, 4.6 Hz, 1H), 7.67 (s, HRMS(B)(1-(5-methyl-1-phenyl-1H- 0.5H), 7.61 (s, 0.5H), 7.55 (dd, J = 8.5, 6.7(M + H) pyrazol-4- Hz, 2H), 7.52-7.47 (m, 1H), 7.44 (ddd, J = 407.2202yl)ethylamino)pyrimidin-4- 8.1, 3.3, 1.4 Hz, 2H), 7.40 (d, J = 5.8 Hz,yl)oxazolidin-2-one 1H), 5.17 (dq, J = 10.4, 6.9 Hz, 1H), 4.83- 4.77 (m,1H), 4.45-4.34 (m, 2H), 2.66 (td, J = 7.0, 3.5 Hz, 0.5H), 2.45 (br s,0.5H), 2.32 (s, 1.5H), 2.31 (s, 1.5H), 1.59 (dd, J = 6.8, 1.7 Hz, 3H),1.01 (d, J = 7.0 Hz, 1.5H), 0.94-0.85 (m, 3H), 0.81 (d, J = 6.9 Hz,1.5H). 259: (R)-3-(2-((S)-1- 8.60 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.10HRMS(B) phenylethylamino)pyrimidin- (d, J = 5.7 Hz, 1H), 7.89 (td, J =7.7, 1.8 (M + H) 4-yl)-4-(pyridin-2- Hz, 1H), 7.46-7.36 (m, 3H),7.33-7.28 362.1617 yl)oxazolidin-2-one (m, 4H), 7.21 (ddd, J = 8.6, 5.5,2.2 Hz, 1H), 5.66 (br s, 1H), 4.79 (t, J = 8.9 Hz, 1H), 4.60 (br s, 1H),4.31 (dd, J = 8.9, 3.8 Hz, 1H), 1.22 (d, J = 6.6 Hz, 3H). 260:(S)-3-(2-((S)-1-(2- 8.51 (d, J = 5.7 Hz, 1H), 7.76-7.51 (m, HRMS(B)fluorophenyl)ethylami- 3H), 7.48-7.37 (m, 2H), 5.71 (q, J = 7.0 (M + H)no)pyrimidin-4-yl)-4- Hz, 1H), 5.06-5.02 (m, 1H), 4.75-4.61 393.2026isopropyloxazolidin-2-one (m, 2H), 2.30 (br s, 1H), 1.89 (d, J = 7.0,3H), 1.10 (d, J = 7.1 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H). 261:(S)-4-isopropyl-3-(2- 8.25-8.05 (m, 2H), 7.83 (dd, J = 8.6, 2.5 HRMS(B)((S)-1-(6-phenoxypyridin- Hz, 1H), 7.50-7.34 (m, 3H), 7.27-7.16 (M + H)3-yl)ethylamino)pyrimidin- (m, 1H), 7.15-7.02 (m, 2H), 6.89 (d, J =420.2019 4-yl)oxazolidin-2-one 8.5 Hz, 1H), 5.10 (q, J = 7.1 Hz, 1H),4.75- 4.61 (m, 1H), 4.41-4.29 (m, 2H), 1.94 (br s, 1H), 1.56 (d, J = 7.1Hz, 3H), 0.78 (br s, 3H), 0.70 (br s, 3H). 262: (S)-3-(5-fluoro-2-(1-8.16 (d, J = 3.5 Hz, 1H), 7.45-7.28 (m, HRMS(B) (4- 4H), 7.09 (tt, J =7.3, 1.1 Hz, 1H), 7.02- (M + H) phenoxyphenyl)ethylami- 6.89 (m, 4H),4.99 (q, J = 6.9 Hz, 1H), 4.58- 395.1507 no)pyrimidin-4- 4.48 (m, 2H),4.18 (ddd, J = 9.7, 8.5, 7.2 yl)oxazolidin-2-one Hz, 1H), 3.99 (br s,1H), 1.52 (d, J = 6.9 Hz, 3H). 263: (S)-3-(2-(1-(4- 8.09 (d, J = 5.8 Hz,1H), 7.43-7.29 (m, HRMS(B) phenoxyphenyl)ethylami- 5H), 7.09 (tt, J =7.3, 1.1 Hz, 1H), 7.00- (M + H) no)pyrimidin-4- 6.90 (m, 4H), 5.07 (q, J= 7.0 Hz, 1H), 4.53- 377.1600 yl)oxazolidin-2-one 4.41 (m, 2H), 4.21(ddd, J = 10.5, 9.2, 7.0 Hz, 1H), 4.01 (br s, 1H), 1.53 (d, J = 7.0 Hz,3H). 264: (4S)-4-isopropyl-3-(2- 8.12 (dd, J = 8.5, 5.8 Hz, 1H), 7.35(dd, J = ((1-(4-((tetrahydro-2H- 5.8, 1.0 Hz, 1H), 7.32-7.19 (m, 2H),6.95- pyran-4- 6.86 (m, 2H), 4.98 (dq, J = 25.6, 7.2 Hz,yl)oxy)phenyl)ethyl)amino) 1H), 4.68 (br s, 0.5H), 4.59-4.48 (m,pyrimidin-4-yl)oxazolidin- 1.5H), 4.39-4.25 (m, 2H), 4.01-3.90 (m, 2-one2H), 3.65-3.53 (m, 2H), 2.74-2.61 (m, 0.5H), 2.08-1.96 (m, 2H), 1.95 (brs, 0.5H), 1.78-1.64 (m, 2H), 1.50 (dd, J = 6.9, 1.6 Hz, 3H), 1.01 (d, J= 7.0 Hz, 1.5H), 0.88 (d, J = 6.9 Hz, 1.5H), 0.75 (br s, 1.5H), 0.62 (brs, 1.5H). 265: (S)-3-(2-((S)-1-(4-(4- 8.14 (d, J = 5.8 Hz, 1H), 7.37 (d,J = 5.8 HRMS(B) fluorophenoxy)phenyl)eth- Hz, 1H), 7.36-7.31 (m, 2H),7.12-7.05 (M + H) ylamino)pyrimidin-4-yl)-4- (m, 2H), 7.01-6.94 (m, 2H),6.94-6.89 437.1981 isopropyloxazolidin-2-one (m, 2H), 5.06 (q, J = 7.0Hz, 1H), 4.71 (br s, 1H), 4.41-4.29 (m, 2H), 1.99 (br s, 1H), 1.52 (d, J= 7.0 Hz, 3H), 0.77 (br s, 3H), 0.67 (br s, 3H). 266:(R)-3-(2-((S)-1-(4- 8.46 (d, J = 5.8 Hz, 1H), 7.84-7.73 (m, HRMS(B)bromophenyl)ethylamino) 5H), 7.72-7.67 (m, 1H), 7.64 (dd, J = 7.1, (M +H) pyrimidin-4-yl)-4- 1.8 Hz, 2H), 7.59-7.53 (m, 2H), 5.92 (dd, 439.0762phenyloxazolidin-2-one J = 8.6, 4.0 Hz, 1H), 5.13 (t, J = 8.7 Hz, 1H),4.98 (q, J = 8.4, 7.5 Hz, 1H), 4.55 (dd, J = 8.7, 4.0 Hz, 1H), 1.58 (d,J = 7.0 Hz, 3H). 267: (R)-3-(2-((S)-1- 8.60 (d, J = 2.5 Hz, 1H), 8.55(dd, J = 4.8, HRMS(B) phenylethylamino)pyrimidin- 1.5 Hz, 1H), 8.12 (d,J = 5.8 Hz, 1H), 7.81 (M + H) 4-yl)-4-(pyridin-3- (dt, J = 7.8, 2.0 Hz,1H), 7.54-7.47 (m, 362.1615 yl)oxazolidin-2-one 1H), 7.41 (d, J = 5.8Hz, 1H), 7.36-7.25 (m, 4H), 7.25-7.17 (m, 1H), 5.60 (br s, 1H), 4.80 (t,J = 8.9 Hz, 1H), 4.61 (br s, 1H), 4.27 (dd, J = 9.0, 4.1 Hz, 1H), 1.25(br d, J = 7.5 Hz, 3H). 268: (R)-3-(2-((S)-1- 8.61-8.60 (m, 2H), 8.14(d, J = 5.8 Hz, HRMS(B) phenylethylamino)pyrimidin- 1H), 7.43 (d, J =5.8 Hz, 1H), 7.42-7.37 (M + H) 4-yl)-4-(pyridin-4- (m, 2H), 7.32 (t, J =7.5 Hz, 2H), 7.28- 362.1610 yl)oxazolidin-2-one 7.17 (m, 3H), 5.57 (brs, 1H), 4.80 (t, J = 9.0 Hz, 1H), 4.55 (br s, 1H), 4.22 (dd, J = 9.0,4.1 Hz, 1H), 1.20(br s, 3H). 269: (S)-3-(2-((S)-1-(3- 8.46 (d, J = 5.7Hz, 1H), 7.73 (d, J = 5.8 HRMS(B) methoxyphenyl)ethylami- Hz, 1H),7.64-7.52 (m, 5H), 7.48 (t, J = (M + H) no)pyrimidin-4-yl)-4- 7.8 Hz,1H), 7.11-7.03 (m, 3H), 6.18 (dd, 391.1771 phenyloxazolidin-2-one J =8.7, 3.7 Hz, 1H), 5.25-5.13 (m, 2H), 4.60 (dd, J = 8.7, 3.7 Hz, 1H),4.10 (s, 3H), 1.81 (d, J = 7.0 Hz, 3H). 270: (4S)-3-(2-(1- 8.50-8.45 (m,1H), 7.95 (ddt, J = 7.6, 5.3, HRMS(B) (biphenyl-4- 2.3 Hz, 3H),7.83-7.64 (m, 8H), 7.63- (M + H) yl)ethylamino)pyrimidin-4- 7.54 (m,2H), 7.49 (dd, J = 4.9, 3.0 Hz, 465.2284 yl)-5,5-dimethyl-4- 2H), 5.83(s, 0.5H), 5.57 (s, 0.5H), 5.29- phenyloxazolidin-2-one 5.24 (m, 0.5H),5.04-4.99 (m, 0.5H), 2.02 (s, 1.5H), 1.85-1.84 (m, 3H), 1.62 (d, J = 7.0Hz, 1.5H), 1.35 (d, J = 3.3 Hz, 3H). 271: (S)-3-(2-((S)-1-(4- 8.15 (d, J= 5.8 Hz, 1H), 7.41-7.29 (m, HRMS(B) fluorophenyl)ethylami- 2H), 7.25(d, J = 5.8 Hz, 1H), 7.09-6.98 (M + H) no)pyrimidin-4-yl)-4-isopropyl-(m, 2H), 4.96 (q, J = 7.1 Hz, 1H), 4.29 (d, J = 359.18894-methyloxazolidin-2-one 9.0 Hz, 1H), 3.88 (d, J = 8.9 Hz, 1H), 2.17 (brs, 1H), 1.70 (s, 3H), 1.53 (d, J = 7.0 Hz, 3H), 0.70 (br s, 3H), 0.44(br s, 3H). 272: (S)-4,4-dimethyl-3-(2- 8.12 (d, J = 5.8 Hz, 1H),7.35-7.26i (m, HRMS(B) (1-(4-((4-methylpiperazin- 4H), 7.17 (d, J = 5.9Hz, 1H), 5.02 (q, J = (M + H) 1- 6.9 Hz, 1H), 4.06 (q, J = 8.4 Hz, 2H),3.51 425.2661 yl)methyl)phenyl)ethylami- (s, 2H), 2.49 (br s, 8H), 2.28(s, 3H), 1.70 no)pyrimidin-4- (s, 3H), 1.53 (d, J = 7.0 Hz, 3H), 1.15(br s, yl)oxazolidin-2-one 3H). 273: (R)-5,5-dimethyl-3- 8.09 (d, J =5.8 Hz, 1H), 7.50-7.39 (m, HRMS(B) (2-((S)-1-(4-((4- 3H), 7.36 (tt, J =7.1, 1.4 Hz, 1H), 7.30 (s, (M + H) methylpiperazin-1- 4H), 7.21 (br s,2H), 5.22 (br s, 1H), 4.58 501.2971 yl)methyl)phenyl)ethylami- (br s,1H), 3.53 (s, 2H), 2.50 (br s, 8H), no)pyrimidin-4-yl)-4- 2.28 (s, 3H),1.52 (s, 3H), 1.19 (d, J = 6.8 phenyloxazolidin-2-one Hz, 3H), 0.99 (s,3H). 274: (S)-5,5-dimethyl-3-(2- 8.08 (d, J = 5.8 Hz, 1H), 7.45 (d, J =5.8 HRMS(B) ((S)-1-(4-((4- Hz, 1H), 7.38-7.23 (m, 3H), 7.1 6 (t, J =(M + H) methylpiperazin-1- 7.5 Hz, 4H), 7.00 (br s, 2H), 5.51 (s, 1H),501.2981 yl)methyl)phenyl)ethylami- 4.89-4.83 (m, 1H), 3.49 (d, J = 2.3Hz, no)pyrimidin-4-yl)-4- 2H), 2.50 (br s, 8H), 2.29 (s, 3H), 1.67 (s,phenyloxazolidin-2-one 3H), 1.44 (d, J = 6.9 Hz, 3H), 1.00 (s, 3H). 275:(S)-4-isopropyl-4- 8.14 (d, J = 5.9 Hz, 1H), 7.29 (s, 4H), 7.24methyl-3-(2-((S)-1-(4-((4- (d, J = 5.9 Hz, 1H), 4.97 (p, J = 7.0 Hz,methylpiperazin-1- 1H), 4.60 (br s, 1H), 4.29 (d, J = 8.8 Hz,yl)methyl)phenyl)ethylami- 1H), 3.88 (d, J = 9.0 Hz, 1H), 3.51 (s, 2H),no)pyrimidin-4- 2.59 (br s, 8H), 2.28 (s, 3H), 1.71 (s, 3H),yl)oxazolidin-2-one 1.52 (d, J = 6.9 Hz, 3H), 0.70 (br s, 3H), 0.39 (brs, 3H). 276: (S)-4-isopropyl-5,5- 8.14 (d, J = 5.8 Hz, 1H), 7.39-7.20(m, HRMS(B) dimethyl-3-(2-(((S)-1-(4- 5H), 5.09 (q, J = 7.0 Hz, 1H),4.49 (br s, (M + H) ((4-methylpiperazin-1- 1H), 3.52 (s, 2H), 2.57 (brs, 8H), 2.32 (s, 453.2975 yl)methyl)phenyl)ethyl)ami- 3H), 2.03 (br s,1H), 1.54 (s, 3H), 1.51 (d, J = no)pyrimidin-4- 7.0 Hz, 3H), 1.42 (s,3H), 0.75 (br s, 3H), yl)oxazolidin-2-one 0.62 (br s, 3H). 277:(S)-4-isopropyl-3-(2- 8.60 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 8.16 HRMS(B)((S)-1-(4-(pyridin-2- (d, J = 5.8 Hz, 1H), 7.94-7.86 (m, 3H), (M + H)yl)phenyl)ethylami- 7.84 (dt, J = 7.9, 1.2 Hz, 1H), 7.51-7.43 404.2089no)pyrimidin-4-yl)oxazolidin-2- (m, 2H), 7.41-7.32 (m, 2H), 5.12 (q, J =one 7.0 Hz, 1H), 4.67 (br s, 1H), 4.40-4.18 (m, 2H), 1.83 (br s, 1H),1.58 (d, J = 7.1 Hz, 3H), 0.68 (br s, 3H), 0.56 (br s, 3H). 278:(S)-4-isopropyl-3-(2- 8.60 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 5.8 HRMS(B)((S)-1-(6-phenylpyridin-3- Hz, 1H), 7.95-7.89 (m, 2H), 7.87 (dd, J =(M + H) yl)ethylamino)pyrimidin-4- 8.2, 2.3 Hz, 1H), 7.81 (dd, J = 8.3,0.8 Hz, 404.2079 yl)oxazolidin-2-one 1H), 7.55-7.42 (m, 3H), 7.40 (d, J= 5.8 Hz, 1H), 5.16 (q, J = 7.1 Hz, 1H), 4.66 (br s, 1H), 4.40-4.22 (m,2H), 1.74 (br s, 1H), 1.62 (d, J = 7.0 Hz, 3H), 0.67 (br s, 3H), 0.57(br s, 3H). 279: (S)-4-isopropyl-3-(2- 8.81 (dd, J = 4.3, 1.6 Hz, 1H),8.32 (dt, J = HRMS(B) ((S)-1-(quinolin-6- 8.2, 1.1 Hz, 1H), 8.18 (d, J =5.8 Hz, 1H), (M + H) yl)ethylamino)pyrimidin-4- 8.01 (d, J = 8.7 Hz,1H), 7.89-7.76 (m, 378.1930 yl)oxazolidin-2-one 2H), 7.53 (dd, J = 8.3,4.4 Hz, 1H), 7.37 (d, J = 5.8 Hz, 1H), 5.24 (q, J = 7.1 Hz, 1H), 4.59(br s, 1H), 4.30 (t, J = 8.7 Hz, 1H), 4.22 (br s, 1H), 1.64 (d, J = 7.1Hz, 3H), 1.49 (br s, 1H), 0.35 (br s, 6H). 280: (S)-4-isopropyl-3-(2-8.81 (dd, J = 4.3, 1.7 Hz, 1H), 8.34 (dt, J = HRMS(B)((S)-1-(quinolin-7- 8.4, 1.2 Hz, 1H), 8.13 (d, J = 5.9 Hz, 1H), (M + H)yl)ethylamino)pyrimidin-4- 8.00 (d, J = 1.6 Hz, 1H), 7.93 (d, J = 8.5378.1941 yl)oxazolidin-2-one Hz, 1H), 7.68 (dd, J = 8.6, 1.8 Hz, 1H),7.50 (dd, J = 8.3, 4.4 Hz, 1H), 7.36 (d, J = 5.8 Hz, 1H), 5.23-5.17 (m,1H), 4.50 (br d, J = 84.2 Hz, 1H), 4.35-4.25 (m, 1H), 4.19 (br s, 1H),2.68 (pd, J = 7.0, 3.5 Hz, 1H), 1.65 (d, J = 7.0 Hz, 3H), 1.01 (d, J =7.0 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H). 281: (S)-3-(2-((S)-1-(4- 8.17 (d,J = 5.8 Hz, 1H), 7.81-7.71 (m, HRMS(B) benzoylphenyl)ethylami- 4H),7.69-7.61 (m, 1H), 7.59-7.49 (m, (M + H) no)pyrimidin-4-yl)-4- 4H), 7.39(d, J = 5.8 Hz, 1H), 5.15 (q, J = 431.2072 isopropyloxazolidin-2-one 7.1Hz, 1H), 4.67 (br s, 1H), 4.41-4.23 (m, 2H), 1.75 (br s, 1H), 1.58 (d, J= 7.1 Hz, 3H), 0.69 (br s, 3H), 0.61 (br s, 3H). 282:(S)-3-(2-((S)-1-(3- 8.18 (d, J = 7.1 Hz, 1H), 7.75 (d, J = 7.3 HRMS(B)fluoro-4-(2-methyl-1H- Hz, 1H), 7.71-7.62 (m, 3H), 7.58 (dd, J = (M + H)imidazol-1- 10.9, 1.9 Hz, 1H), 7.51 (dd, J = 8.2, 1.8 Hz, 425.2093yl)phenyl)ethylami- 1H), 5.33 (br s, 1H), 4.81-4.73 (m, 1H),no)pyrimidin-4-yl)-4- 4.46-4.36 (m, 2H), 2.54 (s, 3H), 2.03 (brisopropyloxazolidin-2-one s, 1H), 1.64 (d, J = 7.0 Hz, 3H), 0.84 (br d,J = 7.2 Hz, 3H), 0.70 (br d, J = 7.2 Hz, 3H). 283:(4S)-4-isopropyl-3-(2- 8.15 (dd, J = 8.9, 5.8 Hz, 1H), 7.60-7.50 HRMS(B)(1-(4-(2-methyl-1H- (m, 2H), 7.42-7.32 (m, 3H), 7.14 (dd, J = (M+)imidazol-1- 13.3, 1.5 Hz, 1H), 6.96 (dd, J = 3.5, 1.5 Hz, 406.2217yl)phenyl)ethylami- 1H), 5.17 (q, J = 7.1 Hz, 0.5H), 5.07 (d, J =no)pyrimidin-4-yl)oxazolidin-2- 7.4 Hz, 0.5H), 4.71 (br s, 0.5H), 4.50(br s, one 0.5H), 4.40-4.24 (m, 2H), 2.67 (ddq, J = 10.6, 7.0, 3.6 Hz,0.5H), 2.323 (s, 1.5H), 2.321 (s, 1.5H), 1.95 (br s, 0.5H), 1.58 (dd, J= 7.0, 2.3 Hz, 3H), 1.02 (d, J = 7.0 Hz, 1.5H), 0.88 (d, J = 6.9 Hz,1.5H), 0.76 (br s, 1.5H), 0.64 (br s, 1.5H). 284: (S)-3-(2-(((R)-1-HRMS(B) cyclopentylethyl)ami- m/z no)pyrimidin-4-yl)-4- 319.2133isopropyloxazolidin-2-one (M + H)+, RT = 2.68 min. 285:(S)-3-(2-(((S)-1-(4- HRMS(B) (dimethylamino)phenyl)eth- m/zyl)amino)pyrimidin-4-yl)- 370.2227 4-isopropyloxazolidin-2- (M + H)+,one RT = 2.47 min. 286: N-(3-((S)-1-((4-((S)- HRMS(B) 4-isopropyl-2- m/zoxooxazolidin-3- 384.2032 yl)pyrimidin-2-yl)amino) (M + H)+,Ethylphenyl)acetamide RT = 1.97 min 287: (S)-3-(2-(((S)-1-(1H- HRMS(B)benzo[d]imidazol-2- m/z yl)ethyl)amino)pyrimidin-4- 367.1887yl)-4-isopropyloxazolidin- (M + H)+ 2-one RT = 2.39 min. 288:(S)-3-(2-(((S)-1-(4- HRMS(B) ((4- m/z chlorophenyl)sulfonyl)phe-501.1343, nyl)ethyl)amino)pyrimidin- (M + H)+ 4-yl)-4- RT = 2.68isopropyloxazolidin-2-one min. 289: (S)-4-isopropyl-3-(2- HRMS(B)(((S)-1-(4- m/z nitrophenyl)ethyl)ami- 372.1672,no)pyrimidin-4-yl)oxazolidin-2- (M + H)+, one RT = 2.59 min. 290:(S)-3-(2-(((S)-1-(4- HRMS(B) aminophenyl)ethyl)amino) m/zpyrimidin-4-yl)-4- 342.1931, isopropyloxazolidin-2-one (M + H)+, RT =2.17 min 291: (S)-4-isopropyl-3-(2- HRMS(B) (((S)-1-(5-(methylthio)- m/z1,3,4-oxadiazol-2- 365.1367, yl)ethyl)amino) (M + H)+,pyrimidin-4-yl)oxazolidin- RT = 1.88 2-one min. 292:(S)-4-isopropyl-3-(2- (CDCl₃) δ 8.15 (d, J = 5.9 Hz, 1H), 7.87- HRMS(B)(((S)-1-(5-phenyl-1,3,4- 7.74 (m, 2H), 7.51 (d, J = 5.9 Hz, 1H), 7.46-m/z thiadiazol-2-yl)ethyl) 7.28 (m, 3H), 6.39 (b, 1H), 5.43 (s, 1H),411.1596 amino) pyrimidin-4- 4.58 (dt, J = 8.3, 3.3 Hz, 1H), 4.29-4.12(M + H)+, yl)oxazolidin-2-one (m, 2H), 1.94-1.80 (b, 1H), 1.74 (d, J =RT = 2.54 7.0 Hz, 3H), 0.69 (d, J = 6.8 Hz, 3H), 0.60 min. (d, J = 7.2Hz, 3H) 293: (S)-3-{2-[1-(5-Chloro- HRMS(B) 1H-benzoimidazol-2-yl)- m/zethylamino]-pyrimidin-4- 400.1414, yl}-4-isopropyl-oxazolidin- RT = 2.042-one min. 294: (S)-3-(2-{(S)-1-[5- (CDCl₃) δ 8.22 (d, J = 5.7 Hz, 1.0H), 7.52 HRMS(B) (2,2-Dimethyl-propyl)- (d, J = 5.8 Hz, 0.95 H), 5.92(s, 0.96 H), m/z isoxazol-3-yl]-ethylamino}- 5.50 (d, J = 7.5 Hz, 0.97H), 5.22 (s, 387.2271 pyrimidin-4-yl)-4- 0.83H), 4.72 (d, J = 8.3 Hz,1.0 H), 4.42- isopropyl-oxazolidin-2-one 4.20 (m, 2.06 H), 3.51 (s, 0.27H), 2.61 (s, 2.05 H), 1.62 (d, J = 7.0 Hz, 4.13 H), 0.97 (s, 8.95 H),0.90 (d, J = 7.0 Hz, 2.56 H), 0.80 (d, J = 7.0 Hz, 2.93 H). 295:(4S)-4-isopropyl-3-(2- (CDCl₃) δ 8.93 (d, J = 5.9 Hz, 4H), 8.26- HRMS(B)(1-(5-phenylpyrimidin-2- 8.17 (m, 2H), 7.64-7.44 (m, 12H), 6.41 m/zyl)ethylamino)pyrimidin-4- (br s, 1H), 5.31 (br s, 1H), 4.79-4.65 (m,405.2024 yl)oxazolidin-2-one 2H), 4.41-4.24 (m, 4H), 2.65 (dddd, J = and27.4, 14.1, 7.1, 3.5 Hz, 1H), 2.20 (br s, 405.2025 1H), 1.75-1.64 (m,4H), 1.07-0.85 (m, (M + H)+. 9H), 0.78 (s, 3H). 296: 4-{(S)-1-[4-((S)-4-HRMS(B) lsopropyl-2-oxo- (M+) = oxazolidin-3-yl)-pyrimidin- 467.25332-ylamino]-ethyl}- RT.: 2.83 piperidine-1-carboxylic min. acid benzylester 297: (S)-3-(2-((S)-1-(5- HRMS(B) bromopyridin-2- m/zyl)ethylamino)pyrimidin-4- 406.0870 yl)-4-isopropyloxazolidin- (M + H)+.2-one. RT.: 2.50 min. 298: 3-(5-fluoro-2-((1-(5- HRMS(B) (4-fluoro-3-m/z methylphenyl)pyridin-2- 412.1578 yl)ethyl)amino)pyrimidin-4- (M +H)+. yl)oxazolidin-2-one RT.: 2.35 min. 299: 3-(2-(1-(5-(4- HRMS(B)fluoropnenoxy)pyrimidin- m/z 2-yl)ethylamino)pyrimidin- 411.15724-yl)oxazolidin-2-one. (M + H)+. RT.: 2.25 min. 300:3-(5-fluoro-2-(1-(5-(4- HRMS(B) fluoropnenoxy)pyrimidin- m/z2-yl)ethylamino)pyrimidin- 415.1320 4-yl)oxazolidin-2-one. (M + H)+.RT.: 2.26 min. 301: (4S)-3-(2-(1-(5-(2,4- (CDCl₃) δ 8.45 (d, J = 4.6 Hz,4H), 8.21 (d, MS m/z difluorobenzyloxy)pyrimidin- J = 5.8 Hz, 2H),7.53-7.41 (m, 4H), 6.93 471.8 2- (ddddd, J = 19.9, 9.8, 8.7, 2.6, 1.2Hz, 4H), (M + H)+. yl)ethylamino)pyrimidin-4- 6.21 (s, 1H), 6.11 (s,1H), 5.21 (br s, 2H), yl)-4-isopropyloxazolidin- 5.18 (s, 2H), 5.16 (s,2H), 4.74 (dt, J = 7.7, 2-one 3.3 Hz, 1H), 4.66 (d, J = 7.4 Hz, 1H),4.38- 4.24 (m, 4H), 2.65 (ddq, J = 10.5, 7.1, 3.5 Hz, 1H), 2.30 (br s,1H), 1.65-1.59 (m, 6H), 1.01 (d, J = 7.0 Hz, 3H), 0.89 (dq, J = 7.6,4.9, 4.4 Hz, 6H), 0.79 (d, J = 6.5 Hz, 3H). 302: (S)-3-(2-{(S)-1-[4-(4-LC-MS Fluoro-phenoxy)- m/z cyclohexyl]-ethylamino}- 442.53pyrimidin-4-yl)-4- (M + H)+; isopropyl-oxazolidin-2-one RT.: 1.77 min.303: (4S)-3-(2-(1-(5-(5- (CDCl₃) δ 8.62-8.49 (m, 6H), 8.44-8.36 HRMS(B)bromopyridin-3- (m, 2H), 8.22 (dd, J = 5.7, 0.6 Hz, 2H), m/zyloxy)pyrimidin-2- 7.57-7.46 (m, 4H), 6.14 (br s, 2H), 5.33 500.1038yl)ethylamino)pyrimidin-4- (br s, 2H), 4.76 (dt, J = 8.2, 3.4 Hz, 1H),and yl)-4-isopropyloxazolidin- 4.67 (s, 1H), 4.40-4.26 (m, 4H), 2.67(pd, 500.1034 2-one J = 7.0, 3.4 Hz, 1H), 2.32 (br s, 1H), 1.69- (M +H)+. 1.61 (m, 6H), 1.02 (d, J = 7.0 Hz, 3H), 0.99- 0.80 (m, 9H). 304:(S)-3-(2-((S)-1-(5- (CDCl₃) δ 8.58 (s, 2H), 8.12 (d, J = 5.8 Hz, LC-MSchloropyrimidin-2- 1H), 7.40 (d, J = 5.8 Hz, 1H), 5.97 (br s, m/z 363.1yl)ethylamino)pyrimidin-4- 1H), 5.17 (br s, 1H), 4.63 (dt, J = 8.0, 3.2(M + H)+; yl)-4-isopropyloxazolidin- Hz, 1H), 4.29-4.15 (m, 2H), 2.10(br s, RT.: 1.39 2-one. 1H), 1.50-1.46 (m, 3H), 0.88-0.66 (m, min. 6H).305: (S)-3-(2-((S)-1-(5-(3- (CDCl₃) δ 8.36 (s, 2H), 8.13 (s, 1H), 7.41HRMS(B) chloro-4- (d, J = 5.4 Hz, 1H), 7.15-7.00 (m, 2H), m/zfluorophenoxy)pyrimidin- 6.85 (ddd, J = 9.0, 3.7, 3.0 Hz, 1H), 6.08473.1484 2-yl)ethylamino)pyrimidin- (s, 1H), 5.21 (br s, 1H), 4.66 (dt,J = 8.3, (M + H)+. 4-yl)-4- 3.4 Hz, 1H), 4.30-4.16 (m, 2H), 2.25 (brisopropyloxazolidin-2-one. s, 1H), 1.56-1.51 (m, 3H), 0.85-0.78 (m, 3H),0.77-0.70 (m, 3H). 306: (4S)-4-isopropyl-3-(2- HRMS(B) (1-(5-(pyridin-3-m/z yloxy)pyrimidin-2- 422.1938, yl)ethylamino)pyrimidin-4- RTyl)oxazolidin-2-one 1.91 min and 422.1944, RT 2.01 min (M + H)+. 307:(4S)-3-(2-(1-(5-(3- (CDCl₃) δ 8.43 (d, J = 4.9 Hz, 4H), 8.21 (d, HRMS(B)fluorobenzyloxy)pyrimidin- J = 5.7 Hz, 2H), 7.49-7.34 (m, 4H), 7.26- m/z2-yl)ethylamino)pyrimidin- 7.02 (m, 6H), 6.20 (br s, 1H), 6.11 (br s,453.2048 4-yl)-4- 1H), 5.22 (br s, 2H), 5.16 (s, 2H), 4.74 (dt, andisopropyloxazolidin-2-one J = 7.7, 3.3 Hz, 1H), 4.66 (br s, 1H), 4.38-453.2047 4.23 (m, 4H), 2.66 (heptd, J = 7.0, 3.5 Hz, (M + H)+. 1H), 2.26(br s, 1H), 1.64-1.58 (m, 6H), 1.00 (d, J = 7.0 Hz, 3H), 0.94-0.85 (m,6H), 0.78 (br s, 3H). 308: (S)-3-(2-((S)-1-(5- HRMS(B) iodopyrimidin-2-m/z yl)ethylamino)pyrimidin-4- 454.0614 yl)-4-isopropyloxazolidin- (M+).RT 2-one. 2.35 min 309: (4S)-4-isopropyl-3-(2- HRMS(B) (1-(5-(5- m/z(trifluoromethyl)pyridin-2- 490.1800, yloxy)pyrimidin-2- RTyl)ethylamino)pyrimidin-4- 2.17 min yl)oxazolidin-2-one and 490.1795, RT2.23 min (M + H)+. 310: (4S)-4-isopropyl-3-(2- HRMS(B) (1-(pyrimidin-2-m/z yl)ethylamino)pyrimidin-4- 329.1728, yl)oxazolidin-2-one RT 1.81 minand 329.1726, RT 1.93 min (M + H)+. 311: (4S)-3-(2-(1-(4-(4- (CDCl₃) δ8.56 (dd, J = 5.7, 2.3 Hz, 2H), HRMS(B) fluorophenoxy)pyrimidin- 8.20(dd, J = 5.7, 4.0 Hz, 2H), 7.46 (dd, J = m/z 2-yl)ethylamino)pyrimidin-5.7, 4.4 Hz, 2H), 7.20-7.00 (m, 8H), 6.71 439.1887 4-yl)-4- (dd, J =5.7, 2.0 Hz, 2H), 6.03 (br s, 1H), and isopropyloxazolidin-2-one 5.87(br s, 1H), 5.11 (br s, 2H), 4.72-4.61 439.1887 (m, 2H), 4.40-4.23 (m,4H), 2.59 (ddp, J = (M + H)+. 10.5, 7.1, 3.5 Hz, 1H), 2.21 (br s, 1H),1.59-1.55 (m, 6H), 1.00-0.85 (m, 9H), 0.80 (d, J = 6.3 Hz, 3H). 312:(S)-3-(2-((S)-1-(4- ¹H NMR (400 MHz, CD₃OD) δ ppm 0.63 LCMS m/z(((2S,6R)-2,6- (br. s., 3 H) 0.79 (br. s., 3 H) 1.20 (dd, 454.3dimethylmorpholino)meth- J = 6.26, 2.74 Hz, 6 H) 1.58 (d, J = 7.04 Hz, 3(M + H)+, yl)phenyl)ethylami- H) 2.54-2.82 (m, 2H) 3.73-3.90 (m, 2 H) Rt0.57 no)pyrimidin-4-yl)-4- 4.32 (d, J = 3.52 Hz, 2 H) 4.39 (d, J = 5.87min isopropyloxazolidin-2-one Hz, 2 H) 4.68-4.78 (m, 1 H) 5.15-5.31 (m,1 H) 7.51 (s, 4 H) 7.62-7.76 (m, 1 H) 8.08-8.22 (m, 1 H)

The compounds in Table 9 were prepared using methods substantiallysimilar to those described for the preparation of Examples 1, 113, and171 through 212, including chiral separation to isolate the twodiastereomers.

TABLE 9

313 & 314

315 & 316

317 & 318

319 & 320

321 & 322

323 & 324

325 & 326

327 & 328

329 & 330

331 & 332

333 & 334

335 & 336

337 & 338

339 & 340

341 & 342

343 & 344

345 & 346

347 & 348

349 & 350

351 & 352

353 & 354

355 & 356

357 & 358

359 & 360

361 & 362

363 & 364

365 & 366

367 & 368

369 & 370

371 & 372

373 & 374

375 & 376

377 & 378

379 & 380

381 & 382

383 & 384

385 & 386

387 & 388

389 & 390

391 & 392

393 & 394

395 & 396

397 & 398

399 & 400

401 & 402

403 & 404

405 & 406

407 & 408

409 & 410

411 & 412

413 & 414

415 & 416

417 & 418

419& 420

421 & 422

423 & 424

425 & 426

427

428 & 429

430

431 & 432

433 & 434

435 & 436

437 & 438

439 & 440

441 & 442

443

444 & 445

446 & 447

448 & 449

450 & 451

452 & 453

454 & 455

456

457

458

TABLE 10 Chemical name, NMR chemical shifts, chiral separationconditions and LCMS signal for each compound listed in Table 9. Chiralseparation conditions, peak identification Example: Name and analyticaldata 331 & 314: 4-(4- The chiral separation was carried out with SFC(IA-H, methoxyphenyl)-5,5- 5 μM, 20 × 50 mm) using 28% MeOH in CO2 togive (R)- dimethyl-3-(2-((S)-1-(4-4-(4-methoxyphenyl)-5,5-dimethyl-3-(2-(((S)-1-(4-phenoxyphenyl)ethylami-phenoxyphenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2- no)pyrimidin-4-one and (S)-4-(4-methoxyphenyl)-5,5-dimethyl-3-(2- yl)oxazolidin-2-one(((S)-1-(4-phenoxyphenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one.1^(st) Peak 313: ¹H NMR (400 MHz, CDCl₃) δ 8.03 (dd, J = 5.9, 1.6 Hz,1H), 7.43 (d, J = 5.7 Hz, 1H), 7.30-7.22 (m, 2H), 7.20-7.14 (m, 2H),7.06-7.00 (m, 1H), 6.98 (d, J = 8.2 Hz, 2H), 6.94-6.86 (m, 4H),6.83-6.76 (m, 2H), 5.24 (br s, 1H), 5.01 (s, 1H), 4.57 (br s, 1H), 3.72(s, 3H), 1.46 (s, 3H), 1.24-1.09 (m, 3H), 0.92 (s, 3H); HRMS(B) m/z511.2326 (M + H)+. 2^(nd) Peak 314: ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J= 5.7 Hz, 1H), 7.51 (d, J = 5.7 Hz, 1H), 7.38-7.29 (m, 2H), 7.10 (tt,J =7.3, 1.2 Hz, 1H), 7.06-6.90 (m, 6H), 6.89-6.82 (m, 2H), 6.82-6.75 (m,2H), 5.29 (s, 1H), 5.09 (br s, 1H), 4.80 (br s, 1H), 3.72 (s, 3H), 1.63(s, 3H), 1.48 (d, J = 6.8 Hz, 3H), 1.01 (s, 3H); HRMS(B) m/z 511.2323(M + H)+. 315 & 316: (S)-4-methyl- The chiral separation was carried outwith SFC (IA, 4-phenyl-3-(2-(1-(1- 5 μm, 20 × 250 mm) using 45% iPrOHwith 0.2% Et2NH phenyl-1H-pyrazol-4- in CO2 to give(S)-4-methyl-4-phenyl-3-(2-(((R)-1-(1- yl)ethylamino)pyrimidin-4-phenyl-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-oneyl)oxazolidin-2-one and (S)-4-methyl-4-phenyl-3-(2-(((S)-1-(1-phenyl-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 1st Peak 315: ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d,J = 5.8 Hz, 1 H), 7.63-7.60 (m, 2 H), 7.49-7.44 (m, 4 H), 7.37-7.28 (m,4 H), 7.26-7.22 (m, 2 H), 7.12-7.08 (m, 1 H), 4.94 (br s, 1 H), 4.45 (brs, 1 H), 4.31-4.27 (m, 2 H), 2.19 (s, 3 H), 1.44 (d, J = 6.8 Hz, 3 H);HRMS(B) m/z 441.2036 (M + H)+. 2nd Peak 316: ¹H NMR (400 MHz, CDCl₃) δ8.20 (d, J = 5.8 Hz, 1 H), 7.67-7.63 (m, 3 H), 7.53 (s, 1 H), 7.49- 7.44(m, 3 H), 7.40-7.37 (m, 2 H), 7.33-7.30 (m, 4 H), 4.99 (br s, 1 H), 4.38(br s, 1 H), 4.26 (s, 2 H), 2.00 (s, 3 H), 1.07 (br s, 3 H); HRMS(B) m/z441.2039 (M + H)+. 317 & 318: (R)-4-methyl- The chiral separation wascarried out with SFC (IA, 4-phenyl-3-(2-(1-(1- 5 μm, 20 × 250 mm) with45% iPrOH modified with 0.2% phenyl-1H-pyrazol-4- Et2NH in CO2 to give(R)-4-methyl-4-phenyl-3-(2-(((S)- yl)ethylamino)pyrimidin-4-1-(1-phenyl-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-oneyl)oxazolidin-2-one and (S)-4-methyl-4-phenyl-3-(2-(((S)-1-(1-phenyl-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 1st peak 317: ¹H NMR (400 MHz, CDCl₃) δ 8.20 (d,J = 5.8 Hz, 1 H), 7.68-7.63 (m, 3 H), 7.53 (s, 1 H), 7.49- 7.44 (m, 3H), 7.41-7.37 (m, 2 H), 7.33-7.30 (m, 4 H), 4.98 (br s, 1 H), 4.39 (brs, 1 H), 4.26 (s, 2 H), 2.00 (s, 3 H), 1.07 (br s, 3 H); HRMS(B) m/z441.2037 (M + H)+. 2nd peak 318: ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J =5.8 Hz, 1 H), 7.63-7.60 (m, 2 H), 7.49-7.44 (m, 4 H), 7.36-7.29 (m, 4H), 7.26-7.22 (m, 2 H), 7.12-7.08 (m, 1 H), 5.02 (br s, 1 H), 4.45 (brs, 1 H), 4.31-4.26 (m, 2 H), 2.19 (s, 3 H), 1.44 (d, J = 6.8 Hz, 3 H);HRMS(B) m/z 441.2039 (M + H)+. 319 & 320: (R)-4-(4- Separation wasachieved on a normal phase silica gel fluorophenyl)-3-(2-(1-(1- columnwith 10 to 50% ethylacetate/heptane to give (4-fluorophenyl)-1H-(R)-4-(4-fluorophenyl)-3-(2-(((R)-1-(1-(4-fluorophenyl)- pyrazol-4-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-yl)ethylamino)pyrimidin-4- methyloxazolidin-2-one and(R)-4-(4-fluorophenyl)-3-(2- yl)-4-methyloxazolidin-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4- oneyl)ethyl)amino)pyrimidin-4-yl)-4-methyloxazolidin-2-one. 1st peak 319:¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J = 5.8 Hz, 1 H), 7.53-7.48 (m, 3 H),7.44 (s, 1 H), 7.36 (d, J = 5.8 Hz, 1 H), 7.22-7.17 (m, 2 H), 7.09-7.03(m, 2 H), 7.01-6.95 (m, 2 H), 4.98 (br s, 1 H), 4.33 (br s, 1 H), 4.15(q, J = 8.6 Hz, 2 H), 1.90 (s, 3 H), 1.04 (br s, 3 H); HRMS(B) m/z477.1827 (M + H)+. 2nd peak 320: ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J =5.8 Hz, 1 H), 7.62-7.56 (m, 2 H), 7.45-7.39 (m, 3 H), 7.31-7.26 (m, 2H), 7.18-7.12 (m, 2 H), 6.93 (t, J = 8.6 Hz, 2 H), 5.01 (br s, 1 H),4.50 (br s, 1 H), 4.30- 4.23 (m, 2 H), 2.17 (s, 3 H), 1.45 (d, J = 6.8Hz, 3 H); HRMS(B) m/z 477.1829 (M + H)+. 321 & 322: (S)-4- Separationwas achieved on a normal phase silica gel isopropyl-3-(2-(1-(1-(3-column with 10 to 50% ethylacetate/heptane to give methoxyphenyl)-1H-(S)-4-isopropyl-3-(2-(((R)-1-(1-(3-methoxyphenyl)-1H- pyrazol-4-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneyl)ethylamino)pyrimidin-4- and(S)-4-isopropyl-3-(2-(((S)-1-(1-(3-methoxyphenyl)- yl)oxazolidin-2-one1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2- one. 1st peak321: ¹H NMR (400 MHz, MeOD) δ 8.18 (dd, J = 3.3, 2.5 Hz, 2H), 7.70 (s,1H), 7.42 (d, J = 5.8 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.31 (t, J =2.3 Hz, 1H), 7.27 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 6.89 (ddd, J = 8.1,2.5, 0.9 Hz, 1H), 5.21 (q, J = 6.8 Hz, 1H), 4.81-4.73 (m, 1H), 4.44-4.34(m, 2H), 3.87 (s, 3H), 2.64 (pd, J = 7.0, 3.5 Hz, 1H), 1.61 (d, J = 6.9Hz, 3H), 0.99 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H). HRMS(B)(M + H) 423.2141 Calc'd (M + H) 423.2145 2nd peak 322: ¹H NMR (400 MHz,MeOD) δ 8.18 (d, J = 5.8 Hz, 1H), 8.10 (s, 1H), 7.63 (s, 1H), 7.41 (d, J= 5.8 Hz, 1H), 7.37 (t, J = 8.2 Hz, 1H), 7.28 (t, J = 2.3 Hz, 1H), 7.24(ddd, J = 8.1, 2.1, 0.9 Hz, 1H), 6.88 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H),5.19 (q, J = 6.9 Hz, 1H), 4.74 (dt, J = 7.6, 3.5 Hz, 1H), 4.42-4.28 (m,2H), 3.86 (s, 3H), 2.31 (br s, 1H), 1.61 (d, J = 6.9 Hz, 3H), 0.79 (brs, 3H), 0.75-0.64 (br m, 3H). HRMS(B) (M + H) 423.2139 Calc'd (M + H)423.2145 323 & 324: 4-(4-(1-(4-((S)- Chiral separation was achieved bySFC. (Column: 4-isopropyl-2- Chiralpak-ID (Semi-Prep 20 mm × 250 mm)oxooxazolidin-3- Isocratic: 65% CO2: 35% MeOH (5 mM NH4OH additive)yl)pyrimidin-2- to give (S)-4-isopropyl-3-(2-(((R)-1-(1-(3-ylamino)ethyl)-5-methyl-methoxyphenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin- 1H-pyrazol-1-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-(((S)-1- yl)benzonitrile(1-(3-methoxyphenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 1st peak 323: ¹H NMR(400 MHz, MeOD) δ 8.16 (d, J = 5.8 Hz, 1H), 7.95-7.88 (m, 2H), 7.75 (s,1H), 7.73- 7.67 (m, 2H), 7.40 (d, J = 5.8 Hz, 1H), 5.19 (q, J = 6.9 Hz,1H), 4.79 (td, J = 5.7, 3.5 Hz, 1H), 4.40 (d, J = 5.7 Hz, 2H), 2.65 (pd,J = 7.0, 3.6 Hz, 1H), 2.41 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H), 1.00 (d, J= 7.0 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H). HRMS(B) (M + H) 432.2138 Calc'd(M + H) 432.2148 2nd peak 324: ¹H NMR (400 MHz, MeOD) δ 8.17 (d, J = 5.8Hz, 1H), 7.97-7.84 (m, 2H), 7.77-7.63 (m, 3H), 7.40 (d, J = 5.8 Hz, 1H),5.16 (q, J = 6.8 Hz, 1H), 4.79 (dt, J = 7.5, 3.8 Hz, 1H), 4.43-4.33 (m,2H), 2.41 (s, 4H), 1.59 (d, J = 6.9 Hz, 3H), 0.87 (br d, J = 7.1 Hz,3H), 0.80 (br d, J = 6.9 Hz, 3H). HRMS(B) (M + H) 432.2137 Calc'd (M +H) 432.2148 325 & 326: (S)-3-(2-(1- Chiral separation was achieved bychiral SFC column (3,5-dimethyl-1-phenyl- chromatography (Column AD-H 5mM 20 × 250 mm 1H-pyrazol-4- column 15% MeOH + DEA) to give(S)-3-(2-(((R)-1-(3,5- yl)ethylamino)pyrimidin-4-dimethyl-1-phenyl-1H-pyrazol-4- yl)-4-isopropyloxazolidin-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- 2-one one and(S)-3-(2-(((S)-1-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4- isopropyloxazolidin-2-one.1st peak 325: ¹H NMR (400 MHz, MeOD) δ 8.16 (d, J = 5.8 Hz, 1H),7.57-7.49 (m, 2H), 7.48-7.42 (m, 1H), 7.42-7.38 (m, 3H), 5.12 (q, J =7.0 Hz, 1H), 4.78 (td, J = 5.6, 3.5 Hz, 1H), 4.44-4.36 (m, 2H), 2.63(td, J = 7.0, 3.6 Hz, 1H), 2.34 (s, 3H), 2.32 (s, 3H), 1.59 (d, J = 7.1Hz, 3H), 1.00 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H). HRMS(B)(M + H) 421.2348 Calc'd (M + H) 421.2352 2nd peak 326: ¹H NMR (400 MHz,MeOD) δ 8.18 (d, J = 5.8 Hz, 1H), 7.56-7.49 (m, 2H), 7.48-7.41 (m, 1H),7.40-7.35 (m, 3H), 5.07 (q, J = 7.1 Hz, 1H), 4.78 (dt, J = 7.8, 3.8 Hz,1H), 4.44-4.32 (m, 2H), 2.33 (s, 3H), 2.31 (br s, 1H) 2.29 (s, 3H), 1.59(d, J = 7.1 Hz, 3H), 0.85 (br d, J = 7.0 Hz, 3H), 0.77 (br d, J = 6.9Hz, 3H). HRMS(B) (M + H) 421.2347 Calc'd (M + H) 421.2352 327 & 328:(S)-3-(2-(1-(4- Separation was achieved by reverse HPLC (10-85%(1H-imidazol-1- ACN/water 0.1% NH4OH modifier) to give (S)-3-(2-yl)phenyl)ethylami- (((R)-1-(4-(1H-imidazol-1- no)pyrimidin-4-yl)-4-yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4- isopropyloxazolidin-2-oneisopropyloxazolidin-2-one and (S)-3-(2-(((S)-1-(4-(1H-imidazol-1-yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one. 1st peak 327: ¹H NMR (400 MHz, MeOD) δ8.25-8.00 (m, 2H), 7.53 (d, J = 0.7 Hz, 5H), 7.38 (d, J = 5.9 Hz, 1H),7.15 (s, 1H), 5.04 (q, J = 7.1 Hz, 1H), 4.50 (br s, 1H), 4.40-4.19 (m,2H), 2.68 (pd, J = 7.0, 3.6 Hz, 1H), 1.57 (d, J = 7.0 Hz, 3H), 1.02 (d,J = 7.0 Hz, 3H), 0.87 (d, J = 7.0 Hz, 3H). HRMS(B) (M + H) 393.2042Calc'd (M + H) 393.2039 2nd peak 328: ¹H NMR (400 MHz, MeOD) δ 8.16 (d,J = 5.8 Hz, 1H), 8.10 (t, J = 1.2 Hz, 1H), 7.55 (t, J = 1.4 Hz, 1H),7.52 (s, 4H), 7.38 (d, J = 5.8 Hz, 1H), 7.15 (t, J = 1.2 Hz, 1H), 5.12(q, J = 7.0 Hz, 1H), 4.67 (br s, 1H), 4.44-4.23 (m, 2H), 1.84 (br s,1H), 1.57 (d, J = 7.0 Hz, 3H), 0.71 (br s, 3H), 0.60 (br s, 3H). HRMS(B)(M + H) 393.2026 Calc'd (M + H) 393.2039 329 & 330: (S)-3-(2-(1-(3-Chiral separation was achieved by chiral SFC column fluoro-4-(pyridin-3-chromatography (Column AD-H 5 mM 20 × 250 mm yloxy)phenyl)ethylami-column 15% MeOH + DEA) to give (S)-3-(2-(((R)-1-(3-no)pyrimidin-4-yl)-4-fluoro-4-(pyridin-3-yloxy)phenyl)ethyl)amino)pyrimidin-4-isopropyloxazolidin-2-one yl)-4-isopropyloxazolidin-2-one and(S)-3-(2-(((S)-1-(3-fluoro-4-(pyridin-3-yloxy)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one. 1st peak 329: ¹H NMR (400 MHz, MeOD) δ8.32-8.23 (m, 2H), 8.15 (d, J = 5.8 Hz, 1H), 7.45-7.35 (m, 3H), 7.31(dd, J = 11.8, 2.0 Hz, 1H), 7.26 (dd, J = 8.5, 2.0 Hz, 1H), 7.19 (t, J =8.2 Hz, 1H), 5.15-4.95 (m, 1H), 4.51 (s, 1H), 4.41-4.26 (m, 2H), 2.68(pd, J = 7.1, 3.6 Hz, 1H), 1.56 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 7.1Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H). HRMS(B) (M + H) 438.1935 Calc'd (M +H) 438.1941 2nd peak 330: ¹H NMR (400 MHz, MeOD) δ 8.28 (dd, J = 4.7,1.4 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H), 8.17 (d, J = 5.8 Hz, 1H),7.43-7.40 (m, 2H), 7.36 (ddd, J = 8.4, 2.9, 1.5 Hz, 1H), 7.30 (dd, J =11.8, 2.0 Hz, 1H), 7.25 (dd, J = 8.4, 2.0 Hz, 1H), 7.19 (t, J = 8.2 Hz,1H), 5.10 (q, J = 7.1 Hz, 1H), 4.72 (br s, 1H), 4.43-4.29 (m, 2H), 1.93(br s, 1H), 1.55 (d, J = 7.0 Hz, 3H), 0.78 (br s, 3H), 0.69 (br s, 3H).HRMS(B) (M + H) 438.1928 Calc'd (M + H) 438.1941 331 & 332: (4S)-4-Chiral separation was achieved by chiral SFC columnisopropyl-3-(2-((1-(4- chromatography (Column IA-H 5 mM 20 × 250 mmcolumn ((tetrahydro-2H-pyran-4- 30% MeOH) to give(S)-4-isopropyl-3-(2-(((R)-1-(4- yl)oxy)phenyl)ethyl)amino)((tetrahydro-2H-pyran-4- pyrimidin-4-yl)oxazolidin-yl)oxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2- 2-one one and(S)-4-isopropyl-3-(2-(((S)-1-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one. 1stpeak 331: HRMS(B) (M+) 426.2267, RT = 2.45 min 2nd peak 332: HRMS(B)(M+) 426.2267, RT = 2.37 min 333 & 334: (R)-3-(2-(1- Separation wasachieved on a normal phase silica gel (3,4- column with 10 to 40%ethylacetate/heptane to give dichlorophenyl)ethylami-(R)-3-(2-(((S)-1-(3,4- no)pyrimidin-4-yl)-4-dichlorophenyl)ethyl)amino)pyrimidin-4-yl)-4- phenyloxazolidin-2-onephenyloxazolidin-2-one and (R)-3-(2-(((R)-1-(3,4-dichlorophenyl)ethyl)amino)pyrimidin-4-yl)-4- phenyloxazolidin-2-one 1stpeak 333: ¹H NMR (400 MHz, MeOD) δ 8.49 (d, J = 5.7 Hz, 1H), 7.85-7.74(m, 5H), 7.74-7.68 (m, 1H), 7.66-7.61 (m, 2H), 7.55 (dd, J = 8.3, 2.1Hz, 1H), 5.90 (dd, J = 8.9, 4.0 Hz, 1H), 5.14 (t, J = 8.7 Hz, 1H), 4.97-4.89 (m, 1H), 4.56 (dd, J = 8.8, 4.1 Hz, 1H), 1.60 (d, J = 7.0 Hz, 3H).HRMS(B) (M + H) 429.0899 Calc'd (M + H) 429.0885 2nd peak 334: ¹H NMR(400 MHz, MeOD) δ 8.50 (d, J = 5.7 Hz, 1H), 7.79 (d, J = 5.9 Hz, 1H),7.61 (d, J = 8.4 Hz, 1H), 7.57 (dt, J = 4.6, 2.3 Hz, 3H), 7.45 (dd, J =6.4, 2.9 Hz, 2H), 7.31 (dd, J = 8.3, 2.2 Hz, 1H), 6.16 (dd, J = 8.6, 3.5Hz, 1H), 5.26 (q, J = 6.9 Hz, 1H), 5.16 (t, J = 8.6 Hz, 1H), 4.97-4.88(m, 1H), 4.56 (dd, J = 8.8, 3.6 Hz, 1H), 1.80 (d, J = 7.0 Hz, 3H).HRMS(B) (M + H) 429.0887 Calc'd (M + H) 429.0885 335 & 336: (S)-4-Chiral separation was achieved by chiral SFC columnisopropyl-3-(2-(1-(4- chromatography (Column IA-H 5 mM 20 × 250 mmcolumn (pyridin-3- 40% MeOH, 10 mM NH4OH) to give (S)-4-isopropyl-3-yl)phenyl)ethylami-(2-(((R)-1-(4-(pyridin-3-yl)phenyl)ethyl)amino)pyrimidin-no)pyrimidin-4-yl)oxazolidin-2- 4-yl)oxazolidin-2-one and(S)-4-isopropyl-3-(2-(((S)-1- one(4-(pyridin-3-yl)phenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one.1st peak 335: ¹H NMR (400 MHz, MeOD) δ 8.81 (br s, 1H), 8.52 (br s, 1H),8.14 (br s, 1H), 8.10 (dt, J = 8.2, 1.7 Hz, 1H), 7.71-7.59 (m, 2H),7.58-7.46 (m, 3H), 7.37 (d, J = 5.8 Hz, 1H), 5.04 (dd, J = 11.2, 5.3 Hz,1H), 4.50 (br s, 1H), 4.40-4.19 (m, 2H), 2.69 (ddd, J = 10.4, 7.0, 3.5Hz, 1H), 1.58 (d, J = 7.0 Hz, 3H), 1.03 (d, J = 7.0 Hz, 3H), 0.88 (d, J= 7.0 Hz, 3H). HRMS(B) (M + H) 404.2085 Calc'd (M + H) 404.2086 2nd peak336: ¹H NMR (400 MHz, MeOD) δ 8.82 (br s, 1H), 8.55 (br s, 1H), 8.17 (brs, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.70-7.59 (m, 2H), 7.54 (br s, 1H),7.51-7.45 (m, 2H), 7.38 (d, J = 5.7 Hz, 1H), 5.11 (q, J = 7.0 Hz, 1H),4.66 (br s, 1H), 4.36-4.30 (m, 2H), 1.80 (br s, 1H), 1.58 (d, J = 7.0Hz, 3H), 0.67 (br s, 3H), 0.56 (br s, 3H). HRMS(B) (M + H) 404.2079Calc'd (M + H) 404.2086 337 & 338: (S)-4- Separation was achieved on anormal phase silica gel isopropyl-3-(2-(1-(4- column with 20 to 100%ethylacetate/heptane to give (pyridin-4-(S)-4-isopropyl-3-(2-(((R)-1-(4-(pyridin-4- yl)phenyl)ethylami-yl)phenyl)etnyl)amino)pyrimidin-4-yl)oxazolidin-2-oneno)pyrimidin-4-yl)oxazolidin-2- and(S)-4-isopropyl-3-(2-(((S)-1-(4-(pyridin-4- oneyl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 1st peak 337: ¹HNMR (400 MHz, MeOD) δ 8.58 (br s, 2H), 8.14 (d, J = 5.9 Hz, 1H),7.83-7.66 (m, 4H), 7.60- 7.46 (m, 2H), 7.37 (d, J = 5.8 Hz, 1H),5.15-4.96 (m, 1H), 4.48 (br s, 1H), 4.38-4.15 (m, 2H), 2.69 (ddp, J =10.5, 7.0, 3.5 Hz, 1H), 1.58 (d, J = 7.0 Hz, 3H), 1.03 (d, J = 7.0 Hz,3H), 0.88 (d, J = 6.9 Hz, 3H). HRMS(B) (M + H) 404.2068 Calc'd (M + H)404.2086 2nd peak 338: ¹H NMR (400 MHz, MeOD) δ 8.59 (br s, 2H), 8.17(br s, 1H), 7.80-7.68 (m, 4H), 7.56-7.44 (m, 2H), 7.38 (d, J = 5.8 Hz,1H), 5.11 (q, J = 7.0 Hz, 1H), 4.65 (br s, 1H), 4.31 (dt, J = 17.1, 9.0Hz, 2H), 1.76 (br s, 1H), 1.58 (d, J = 7.1 Hz, 3H), 0.66 (br s, 3H),0.55 (br s, 3H). HRMS(B) (M + H) 404.1939 Calc'd (M + H) 404.2086 339 &340: (S)-4- Separation was achieved on a normal phase silica gelisopropyl-3-(2-(1-(4- column with 40 to 100% ethylacetate/heptane togive (methyl(phenyl)amino)phe- (S)-4-isopropyl-3-(2-(((R)-1-(4-nyl)etnylamino)pyrimidin-(methyl(phenyl)amino)phenyl)ethyl)amino)pyrimidin-4-4-yl)oxazolidin-2-one yl)oxazolidin-2-one and(S)-4-isopropyl-3-(2-(((S)-1-(4-(methyl(phenyl)amino)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 1st peak 339: ¹H NMR (400 MHz, MeOD) δ 8.12 (d, J =5.8 Hz, 1H), 7.37 (d, J = 5.8 Hz, 1H), 7.31-7.18 (m, 4H), 7.03-6.94 (m,4H), 6.91 (tt, J = 7.4, 1.1 Hz, 1H), 4.99-4.93 (m, 1H), 4.57 (br s, 1H),4.42-4.27 (m, 2H), 3.28 (s, 3H), 2.68 (ddq, J = 10.5, 6.9, 3.4 Hz, 1H),1.53 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 7.0 Hz,3H). HRMS(B) (M + H) 432.2390 Calc'd (M + H) 432.2400 2nd peak 340: ¹HNMR (400 MHz, MeOD) 5 8.15 (d, J = 5.8 Hz, 1H), 7.37 (d, J = 5.8 Hz,1H), 7.30-7.18 (m, 4H), 7.02-6.92 (m, 4H), 6.89 (tt, J = 7.3, 1.1 Hz,1H), 5.04 (q, J = 7.0 Hz, 1H), 4.77-4.67 (m, 1H), 4.43- 4.26 (m, 2H),3.27 (s, 3H), 2.11 (br s, 1H), 1.52 (d, J = 7.0 Hz, 3H), 0.79 (br s,3H), 0.68 (br s, 3H). HRMS(B) (M + H) 432.2386 Calc'd (M + H) 432.2400341 & 342: S)-3-(2-(1-(3- Chiral separation was achieved by chiral SFCcolumn fluoro-4-(4-methyl-1H- (IC 20 × 250 nm 45% IPA in CO2, 75 g/minFlow) to give pyrazol-1-(S)-3-(2-(((R)-1-(3-fluoro-4-(4-methyl-1H-pyrazol-1- yl)phenyl)ethylami-yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4- no)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one and (S)-3-(2-(((S)-1-(3-fluoro-isopropyloxazolidin-2-one 4-(4-methyl-1H-pyrazol-1-yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4- isopropyloxazolidin-2-one. 1stpeak 341: ¹H NMR (400 MHz, MeOD) δ 8.15 (d, J = 5.8 Hz, 1H), 7.81 (dt, J= 2.9, 0.9 Hz, 1H), 7.66 (t, J = 8.3 Hz, 1H), 7.56 (s, 1H), 7.40 (d, J =5.8 Hz, 1H), 7.36- 7.25 (m, 2H), 5.01 (d, J = 7.5 Hz, 1H), 4.46 (br s,1H), 4.38-4.25 (m, 2H), 2.68 (pd, J = 7.0, 3.5 Hz, 1H), 2.17 (d, J = 0.6Hz, 3H), 1.56 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 7.1 Hz, 3H), 0.87 (d, J= 6.9 Hz, 3H). HRMS(B) (M + H) 425.2089 Calc'd (M + H) 425.2101 2nd peak342: ¹H NMR (400 MHz, MeOD) δ 8.17 (d, J = 5.8 Hz, 1H), 7.80 (d, J = 2.6Hz, 1H), 7.66 (t, J = 8.3 Hz, 1H), 7.56 (s, 1H), 7.40 (d, J = 5.8 Hz,1H), 7.35-7.26 (m, 2H), 5.10 (q, J = 7.0 Hz, 1H), 4.69 (br s, 1H), 4.43-4.24 (m, 2H), 2.17 (s, 3H), 1.80 (br s,1H), 1.56 (d, J = 7.1 Hz, 3H),0.73 (br s, 3H), 0.62 (br s, 3H). HRMS(B) (M + H) 425.2081 Calc'd (M +H) 424.2101 343 & 344: (S)-3-(2-(1-(4- Chiral separation was achieved bychiral SFC column (3,5-dimethyl-1H-pyrazol- chromatography (Column IA 20× 250 mm column 25% 1- MeOH, 0.2% DEA) to give (S)-3-(2-(((R)-1-(4-(3,5-yl)phenyl)ethylami-dimethyl-1H-pyrazol-1-yl)phenyl)ethyl)amino)pyrimidin-no)pyrimidin-4-yl)-4- 4-yl)-4-isopropyloxazolidin-2-one and(S)-3-(2-(((S)-1- isopropyloxazolidin-2-one(4-(3,5-dimethyl-1H-pyrazol-1- yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one. 1st peak 343: ¹H NMR (400 MHz, MeOD) δ 8.14(d, J = 5.8 Hz, 1H), 7.56-7.48 (m, 2H), 7.41-7.34 (m, 3H), 6.06 (s, 1H),5.07-5.02 (m, 1H), 4.46 (br s, 1H), 4.39- 4.22 (m, 2H), 2.79-2.60 (m,1H), 2.26 (s, 3H), 2.24 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.02 (d, J =7.1 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H). HRMS(B) (M + H) 421.2332 Calc'd(M + H) 421.2352 2nd peak 344: ¹H NMR (400 MHz, MeOD) δ 8.15 (d, J = 5.8Hz, 1H), 7.55-7.47 (m, 2H), 7.41-7.33 (m, 3H), 6.06 (s, 1H), 5.17 (q, J= 7.0 Hz, 1H), 4.74 (br s, 1H), 4.45-4.19 (m, 2H), 2.26 (s, 3H), 2.25(s, 3H), 2.07 (br s, 1H), 1.56 (d, J = 7.0 Hz, 3H), 0.80 (br s, 3H),0.65 (br s, 3H). HRMS(B) (M + H) 421.2335 Calc'd (M + H) 421.2352 345 &346: (S)-4- Chiral separation was achieved by chiral SFC columnisopropyl-3-(2-((1-(5- chromatography (AD-H, 5 uM, 20 × 250 mm column,80 methyl-1,3,4-oxadiazol-2- ml/min, 99 bar, eluting 10% MeOH/CO2) togive (S)-4- yl)ethyl)amino)pyrimidin-4-isopropyl-3-(2-(((R)-1-(5-methyl-1,3,4-oxadiazol-2- yl)oxazolidin-2-oneyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-(((S)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 1st peak 345: HRMS(B)m/z 333.1668 (M + H)+. RT = 1.96 min. 2nd peak 346: HRMS(B) m/z 333.1668(M + H)+. RT = 1.58 min. 347 & 348: (S)-4- Chiral separation wasachieved by chiral SFC column isopropyl-3-(2-((1-(1- chromatography(AD-H, 5 uM, 20 × 250 mm column, 80 methyl-1H-1,2,4-triazol-5- ml/min,99 bar, eluting 10% MeOH/CO2) to give (S)-4- yl)ethyl)amino)pyrimidin-4-isopropyl-3-(2-(((R)-1-(1-methyl-1H-1,2,4-triazol-5-yl)oxazolidin-2-one. yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and(S)- 4-isopropyl-3-(2-(((S)-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 1st peak 347: HRMS(B)m/z 332.1831 (M + H)+. RT = 1.68 min. 2nd peak 348: HRMS(B) m/z 332.1833(M + H)+. RT = 1.57 min. 349 & 350: (S)-3-(2-((1- Chiral separation wasachieved by chiral SFC column (imidazo[2,1- chromatography (AD-H, 5 uM,20 × 250 mm column, 80 b][1,3,4]thiadiazol-6- ml/min, 99 bar, eluting10% MeOH/CO2) to give (S)-3- yl)ethyl)amino)pyrimidin-4-(2-(((R)-1-(imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-4-isopropyloxazolidin-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- 2-one. one and(S)-3-(2-(((S)-1-(imidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one. 1st peak349: HRMS(B) m/z 374.1384 (M + H)+. RT = 2.01 min. 2nd peak 350: ¹H NMR(400 MHz, CDCl₃) δ 8.43 (s, 1H), 8.12 (d, J = 5.8 Hz, 1H), 7.60 (s, 1H),7.38 (d, J = 5.8 Hz, 1H), 5.13 (s, 1H), 4.60 (dt, J = 8.3, 3.3 Hz, 1H),4.33-4.07 (m, 2H), 2.25 (b, 1H), 1.57 (d, J = 6.8 Hz, 3H), 0.84-0.52 (b,6H). HRMS(B) m/z 373.1321 (M+), RT = 1.88 min. 351 & 352:(S)-3-(2-((1-(1- Chiral separation was achieved by chiral SFC columnethyl-1H-1,2,4-triazol-5- chromatography (AD-H, 5 uM, 20 × 250 mmcolumn, 80 yl)ethyl)amino)pyrimidin-4- ml/min, 99 bar, eluting 10%MeOH/CO2) to give (S)-3- yl)-4-isopropyloxazolidin-(2-(((R)-1-(1-ethyl-1H-1,2,4-triazol-5- 2-oneyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one and(S)-3-(2-(((S)-1-(1-ethyl-1H-1,2,4-triazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one 1st peak351: HRMS(B) m/z 346.1985 (M + H)+. RT = 1.89 min. 2nd peak 352: HRMS(B)m/z 346.1983 (M + H)+, RT = 1.75 min. 353 & 354: (S)-3-(2-((1-(4- Chiralseparation was achieved by chiral SFC column ethyl-4H-1,2,4-triazol-3-chromatography (AD-H, 5 uM, 20 × 250 mm column, 80yl)ethyl)amino)pyrimidin-4- ml/min, 99 bar, eluting 10% MeOH/CO2) togive (S)-3- yl)-4-isopropyloxazolidin-(2-(((R)-1-(4-ethyl-4H-1,2,4-triazol-3- 2-oneyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one and(S)-3-(2-(((S)-1-(4-ethyl-4H-1,2,4-triazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one 1st peak353: HRMS(B) m/z 346.1984 (M + H)+. RT = 1.80 min. 2nd peak 354: HRMS(B)m/z 346.1982 (M + H)+, RT = 1.77 min. 355 & 356: (S)-3-(2-((1- Chiralseparation was achieved by chiral SFC column (imidazo[2,1-b]thiazol-6-chromatography (AD-H, 5 uM, 20 × 250 mm column, 75yl)ethyl)amino)pyrimidin-4- ml/min, 120 bar, eluting 20-30% MeOH/CO2) togive yl)-4-isopropyloxazolidin-(S)-3-(2-(((R)-1-(imidazo[2,1-b]thiazol-6- 2-oneyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one and(S)-3-(2-(((S)-1-(imidazo[2,1-b]thiazol-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one 1st peak355: HRMS(B) m/z 373.1436 (M + H)+. RT = 1.92 min. 2nd peak 356: HRMS(B)m/z 373.1439 (M + H)+, RT = 1.84 min. 357 & 358: N-(4-(1-((4- Chiralseparation was achieved by chiral SFC column ((S)-4-isopropyl-2-chromatography (AD-H, 5 uM, 20 × 250 mm column, 80 oxooxazolidin-3-ml/min, 96 bar, eluting 25% MeOH/CO2) to give N-(4- yl)pyrimidin-2-((R)-1-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)amino)ethyl)phenyl)meth- yl)pyrimidin-2- anesulfonamideyl)amino)ethyl)phenyl)methanesulfonamide and N-(4-((S)-1-((4-((S)-4-isopropyl-2-oxooxazolidin-3- yl)pyrimidin-2-yl)amino)ethyl)phenyl)methanesulfonamide 1st peak 357: HRMS(B) m/z420.1689 (M + H)+. RT = 2.08 min. 2nd peak 358: HRMS(B) m/z 420.1687(M + H)+, RT = 1.98 min. 359 & 360: (S)-4- Separation was achieved bysilica gel chromatography isopropyl-3-(2-((1-(3- (10 to 40%EtOAc/heptane) to give (S)-4-isopropyl-3- (pyridin-2-yl)-1,2,4-(2-(((R)-1-(3-(pyridin-2-yl)-1,2,4-oxadiazol-5- oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (S)-yl)ethyl)amino)pyrimidin-4-4-isopropyl-3-(2-(((S)-1-(3-(pyridin-2-yl)-1,2,4-oxadiazol-yl)oxazolidin-2-one 5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1stpeak 359: HRMS(B) m/z 396.1784 (M + H)+. RT = 2.26 min. 2nd peak 360:HRMS(B) m/z 396.1784 (M + H)+, RT = 2.20 min. 361 & 362: (S)-4-Separation was achieved by silica gel chromatographyisopropyl-3-(2-((1-(3-(p- (10 to 40% EtOAc/heptane) to give(S)-4-isopropyl-3- tolyl)-1,2,4-oxadiazol-5-(2-(((R)-1-(3-(p-tolyl)-1,2,4-oxadiazol-5- yl)ethyl)amino)pyrimidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (S)-yl)oxazolidin-2-one4-isopropyl-3-(2-(((S)-1-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 1st peak 361: HRMS(B)m/z 409.1985 (M + H)+. RT = 2.88 min. 2nd peak 362: ¹H NMR (400 MHz,CDCl₃) δ 8.24 (d, J = 5.8 Hz, 1H), 8.03 (d, J = 5.9 Hz, 2H), 7.59 (d, J= 5.8 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 5.41 (b, 1H), 4.67 (dt, J =8.2, 3.3 Hz, 1H), 4.36-4.18 (m, 2H), 2.42 (s, 3H), 2.29-2.13 (m, 1H),1.78 (d, J = 7.2 Hz, 3H), 0.81 (d, J = 7.1 Hz, 3H), 0.73 (d, J = 7.0 Hz,3H). HRMS(B) m/z 409.1985 (M + H)+, RT = 2.85 min. 363 & 364: (S)-4-Chiral separation was achieved by chiral SFC columnisopropyl-3-(2-((1-(4- chromatography (AD-H, 5 uM, 20 × 250 mm column,74 (methylsulfonyl)phenyl)eth- ml/min, 100 bar, eluting 25% MeOH/CO2) togive (S)-4- yl)amino)pyrimidin-4- isopropyl-3-(2-(((R)-1-(4-yl)oxazolidin-2-one (methylsulfonyl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-(((S)-1-(4-(methylsulfonyl)phenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one 1stpeak 363: HRMS(B) m/z 405.1594 (M + H)+. RT = 2.26 min. 2nd peak 364:HRMS(B) m/z 405.1595 (M + H)+, RT = 2.14 min. 365 & 366: (S)-4- Chiralseparation was achieved by chiral SFC column isopropyl-3-(2-((1-(3-chromatography (AD-H, 5 uM, 20 × 250 mm column, 80methyl-1,2,4-oxadiazol-5- ml/min, 100 bar, eluting 20% IPA/CO2) to give(S)-4- yl)ethyl)amino)pyrimidin-4-isopropyl-3-(2-(((R)-1-(3-methyl-1,2,4-oxadiazol-5- yl)oxazolidin-2-oneyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-(((S)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 365: HRMS(B) m/z333.1679 (M + H)+. RT = 2.19 min. 2nd peak 366: HRMS(B) m/z 333.1680(M + H)+, RT = 2.12 min. 367 & 368: (S)-3-(2-((1-(3- Chiral separationwas achieved by chiral SFC column ethylisoxazol-5- chromatography (AD-H,5 uM, 20 × 250 mm column, 79 yl)ethyl)amino)pyrimidin-4- ml/min, 100bar, eluting 20% IPA/CO2) to give (S)-3-(2- yl)-4-isopropyloxazolidin-(((R)-1-(3-ethylisoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)- 2-one4-isopropyloxazolidin-2-one and (S)-3-(2-(((S)-1-(3-ethylisoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one 1st peak 367: HRMS(B) m/z 346.1886 (M + H)+.RT = 2.51 min. 2nd peak 368: HRMS(B) m/z 346.1882 (M + H)+, RT = 2.45min. 369 & 370: (S)-4- Chiral separation was achieved by chiral SFCcolumn isopropyl-3-(2-((1-(3- chromatography (AD-H, 5 uM, 20 × 250 mmcolumn, 75 propyl-1,2,4-oxadiazol-5- ml/min, 100 bar, eluting 20%IPA/CO2) to give (S)-4- yl)ethyl)amino)pyrimidin-4-isopropyl-3-(2-(((R)-1-(3-propyl-1,2,4-oxadiazol-5- yl)oxazolidin-2-oneyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-(((S)-1-(3-propyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 369: HRMS(B) m/z361.1989 (M + H)+. RT = 2.52 min. 2nd peak 370: HRMS(B) m/z 361.1985(M + H)+, RT = 2.49 min. 371 & 372: (S)-3-(2-((1-(3- Chiral separationwas achieved by chiral SFC column cyclopropyl-1,2,4- chromatography(AD-H, 5 uM, 20 × 250 mm column, 80 oxadiazol-5- ml/min, 100 bar,eluting 15% IPA/CO2) to give (S)-3-(2- yl)ethyl)amino)pyrimidin-4-(((R)-1-(3-cyclopropyl-1,2,4-oxadiazol-5- yl)-4-isopropyloxazolidin-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- 2-one one and(S)-3-(2-(((S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one 1st peak371: HRMS(B) m/z 359.1830 (M + H)+. RT = 2.42 min. 2nd peak 372: HRMS(B)m/z 359.1833 (M + H)+, RT = 2.37 min. 373 & 374: (S)-4- Chiralseparation was achieved by chiral SFC column isopropyl-3-(2-((1-(3-chromatography (AD-H, 5 uM, 20 × 250 mm column, 80isopropyl-1,2,4-oxadiazol- ml/min, 100 bar, eluting 20% IPA/CO2) to give(S)-4- 5-yl)ethyl)amino)pyrimidin-isopropyl-3-(2-(((R)-1-(3-isopropyl-1,2,4-oxadiazol-5-4-yl)oxazolidin-2-one yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and(S)- 4-isopropyl-3-(2-(((S)-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 373: HRMS(B) m/z361.1990 (M + H)+. RT = 2.58 min. 2nd peak 374: HRMS(B) m/z 361.1987(M + H)+, RT = 2.54 min. 375 & 376: (S)-3-(2-((1-(1- Chiral separationwas achieved by chiral SFC column ethyl-1H-pyrazol-3- chromatography(AD-H, 5 uM, 20 × 250 mm column, 78 yl)ethyl)amino)pyrimidin-4- ml/min,100 bar, eluting 20% IPA/CO2) to give (S)-3-(2-yl)-4-isopropyloxazolidin-(((R)-1-(1-ethyl-1H-pyrazol-3-yl)ethyl)amino)pyrimidin-4- 2-oneyl)-4-isopropyloxazolidin-2-one and (S)-3-(2-(((S)-1-(1-ethyl-1H-pyrazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one 1st peak 375: HRMS(B) m/z 345.2046 (M + H)+.RT = 2.31 min. 2nd peak 376: HRMS(B) m/z 345.2050 (M + H)+, RT = 2.26min. 377 & 378: (S)-3-(2-((1-(2- Chiral separation was achieved bychiral column hydroxyphenyl)ethyl) chromatography (OJ-H, 4.6 × 250 mmcolumn, 1 amino)pyrimidin-4-yl)-4- ml/min, eluting 25% ethanol/Heptane)to give (S)-3-(2- isopropyloxazolidin-2-one(((R)-1-(2-hydroxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one and (S)-3-(2-(((S)-1-(2-hydroxyphenyl)ethyl)amino)pyrimidin-4-yl)-4- isopropyloxazolidin-2-one1st peak 377: HRMS(B) m/z 343.1767 (M + H)+. RT = 2.41 min. 2nd peak378: HRMS(B) m/z 343.1767 (M + H)+, RT = 2.36 min. 379 & 380: (S)-4-Chiral separation was achieved by chiral SFC columnisopropyl-3-(2-((1-(5- chromatography (AD-H, 5 uM, 20 × 250 mm column,methyl-1-phenyl-1H-1,2,3- 874 ml/min, 100 bar, eluting 30% IPA/CO2) togive (S)- triazol-4-4-isopropyl-3-(2-(((R)-1-(5-methyl-1-phenyl-1H-1,2,3-yl)ethyl)amino)pyrimidin-4-triazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneyl)oxazolidin-2-one and(S)-4-isopropyl-3-(2-(((S)-1-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin- 2-one 1st peak379: HRMS(B) m/z 408.2135 (M + H)+. RT = 2.37 min. 2nd peak 380: HRMS(B)m/z 408.2140 (M + H)+, RT = 2.31 min. 381 & 382: (S)-4- Chiralseparation was achieved by chiral SFC column isopropyl-3-(2-((1-(3-chromatography (AD-H, 5 uM, 20 × 250 mm column, 74phenyl-1,2,4-oxadiazol-5- ml/min, 100 bar, eluting 20%-35% IPA/CO2) togive yl)ethyl)amino)pyrimidin-4-(S)-4-isopropyl-3-(2-(((R)-1-(3-phenyl-1,2,4-oxadiazol-5-yl)oxazolidin-2-one yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and(S)- 4-isopropyl-3-(2-(((S)-1-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 381: HRMS(B) m/z395.1792 (M + H)+. RT = 2.63 min. 2nd peak 382: HRMS(B) m/z 395.1818(M +H)+, RT = 2.58 min. 383 & 384: (S)-3-(2-(((R)- Chiral separation wasachieved by chiral SFC column 1-(1H-pyrrolo[2,3- chromatography (IA, 20× 250 mm column, 74 ml/min, b]pyridin-5- 99 bar, eluting 45% MeOH w ith5 mM NH4OH/CO2) to yl)ethyl)amino)pyrimidin-4- give(S)-3-(2-(((R)-1-(1H-pyrrolo[2,3-b]pyridin-5- yl)-4-isopropyloxazolidin-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- 2-one one and(S)-3-(2-(((S)-1-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one 1st peak383: HRMS(B) m/z 367.1862 (M + H)+. RT = 2.10 min. 2nd peak 384: ¹H NMR(400 MHz, CDCl₃) δ 8.32 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 5.8 Hz, 1H),7.94 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 5.8 Hz, 1H), 7.38 (d, J = 3.5 Hz,1H), 6.46 (d, J = 3.5 Hz, 1H), 5.30-5.08 (m, 1H), 4.73- 4.51 (m, 1H),4.28 (t, J = 8.8 Hz, 1H), 4.19 (dd, J = 9.0, 3.1 Hz, 1H), 1.78 (dd, J =31.8, 17.0 Hz, 1H), 1.66 (d, J = 6.9 Hz, 3H), 0.56 (s, 6H). HRMS(B) m/z367.1870(M + H)+, RT = 2.00 min. 385 & 386: (S)-4- Chiral separation wasachieved by chiral SFC column isopropyl-3-(2-((1-(1- chromatography(AD-H, 5 uM, 20 × 250 mm column, 80 methyl-1H- ml/min, 99 bar, eluting20% IPA/CO2) to give (S)-4- benzo[d]imidazol-5-isopropyl-3-(2-(((R)-1-(1-methyl-1H-benzo[d]imidazol-5-yl)ethyl)amino)pyrimidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (S)-yl)oxazolidin-2-one4-isopropyl-3-(2-(((S)-1-(1-methyl-1H-benzo[d]imidazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 385: HRMS(B)m/z 381.2026 (M + H)+. RT = 2.05 min. 2nd peak 386: HRMS(B) m/z381.2022(M + H)+, RT = 1.96 min. 387 & 388: (S)-4- Chiral separation wasachieved by chiral SFC column isopropyl-3-(2-((1-(2-oxo- chromatography(AD-H, 5 uM, 20 × 250 mm column, 80 2,3-dihydro-1H- ml/min, 100 bar,eluting 25% IPA/CO2) to give (S)-4- benzo[d]imidazol-5-isopropyl-3-(2-(((R)-1-(2-oxo-2,3-dihydro-1H-yl)ethyl)amino)pyrimidin-4-benzo[d]imidazol-5-yl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-oneyl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-(((S)-1-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 387: HRMS(B) m/z383.1811 (M + H)+. RT = 1.90 min. 2nd peak 388: HRMS(B) m/z 383.1815(M +H)+, RT = 1.85 min. 389 & 390: (S)-3-(2-((1- Chiral separation wasachieved by chiral SFC column (benzo[d]thiazol-2- chromatography (ID, 5uM, 20 × 250 mm column, 74 yl)ethyl)amino)pyrimidin-4- ml/min, 100 bar,eluting 35% MeOH/CO2) to give (S)-3- yl)-4-isopropyloxazolidin-(2-(((R)-1-(benzo[d]thiazol-2-yl)ethyl)amino)pyrimidin-4- 2-oneyl)-4-isopropyloxazolidin-2-one and (S)-3-(2-(((S)-1-(benzo[d]thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one 1st peak 389: HRMS(B) m/z 384.1488 (M + H)+.RT = 2.44 min. 2nd peak 390: HRMS(B) m/z 384.1473(M + H)+, RT = 2.36min. 391 & 392: (S)-3-(2-((1- Chiral separation was achieved by chiralSFC column (indolizin-2- chromatography (OJ, 5 uM, 20 × 250 mm column,75 yl)ethyl)amino)pyrimidin-4- ml/min, 120 bar, eluting 15-55% MeOH/CO2)to give yl)-4-isopropyloxazolidin-(S)-3-(2-(((R)-1-(indolizin-2-yl)ethyl)amino)pyrimidin-4- 2-oneyl)-4-isopropyloxazolidin-2-one and (S)-3-(2-(((S)-1-(indolizin-2-yl)ethyl)amino)pyrimidin-4-yl)-4- isopropyloxazolidin-2-one1st peak 391: HRMS(B) m/z 366.1926 (M + H)+. RT = 2.66 min. 2nd peak392: HRMS(B) m/z 366.1918(M + H)+, RT = 2.63 min. 393 & 394: (S)-4-Chiral separation was achieved by chiral SFC columnisopropyl-3-(2-((1-(3-(2- chromatography (AD-H, 5 uM, 20 × 250 mmcolumn, 80 methoxyphenyl)-1,2,4- ml/min, 100 bar, eluting 5-55%MeOH/CO2) to give (S)- oxadiazol-5-4-isopropyl-3-(2-(((R)-1-(3-(2-methoxyphenyl)-1,2,4-yl)ethyl)amino)pyrimidin-4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-yl)oxazolidin-2-one one and (S)-4-isopropyl-3-(2-(((S)-1-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 393: HRMS(B) m/z425.1925 (M + H)+. RT = 2.57 min. 2nd peak 394: HRMS(B) m/z 425.1916(M +H)+, RT = 2.52 min. 395 & 396: (S)-4- Chiral separation was achieved bychiral SFC column isopropyl-3-(2-((1-(3-(3- chromatography (IA, 5 uM, 20× 250 mm column, 74 methoxyphenyl)-1,2,4- ml/min, 100 bar, eluting m25%MeOH/CO2) to give (S)- oxadiazol-5-4-isopropyl-3-(2-(((R)-1-(3-(3-methoxyphenyl)-1,2,4-yl)ethyl)amino)pyrimidin-4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-yl)oxazolidin-2-one one and (S)-4-isopropyl-3-(2-(((S)-1-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 395: HRMS(B) m/z425.1924 (M + H)+. RT = 2.60 min. 2nd peak 396: ¹H NMR (400 MHz, CDCl₃)δ 7.56 (dt, J = 7.7, 1.2 Hz, 1H), 7.49 (dt, J = 3.7, 1.8 Hz, 2H), 7.29(t, J = 8.0 Hz, 2H), 6.96 (ddd, J = 8.3, 2.7, 0.9 Hz, 1H), 5.34 (b, 1H),4.58 (dt, J = 8.2, 3.3 Hz, 1H), 4.37-4.03 (m, 2H), 3.78 (s, 3H), 2.12(b, 1H), 1.68 (d, J = 7.1 Hz, 3H), 0.73 (d, J = 7.1 Hz, 3H), 0.65 (d, J= 7.0 Hz, 3H). HRMS(B) m/z 425.1924(M + H)+, RT = 2.54 min. 397 & 398:(S)-3-(2-((1-(3- Chiral separation was achieved by chiral SFC column(3-fluorophenyl)-1,2,4- chromatography (AD-H, 5 uM, 20 × 250 mm column,75 oxadiazol-5- ml/min, 100 bar, eluting 20% MeOH/CO2) to give (S)-3-yl)ethyl)amino)pyrimidin-4-(2-(((R)-1-(3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl)-4-isopropyloxazolidin-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- 2-one one and(S)-3-(2-(((S)-1-(3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4- isopropyloxazolidin-2-one1st peak 397: HRMS(B) m/z 413.1729 (M + H)+. RT = 2.66 min. 2nd peak398: ¹H NMR (400 MHz, CDCl₃) δ 7.86 (dt, J = 7.8, 1.2 Hz, 1H), 7.77(ddd, J = 9.4, 2.7, 1.5 Hz, 2H), 7.60 (d, J = 5.3 Hz, 1H), 7.46 (td, J =8.0, 5.7 Hz, 1H), 7.22 (tdd, J = 8.4, 2.6, 1.0 Hz, 1H), 5.44 (b, 1H),4.68 (dt, J = 8.3, 3.3 Hz, 1H), 4.44-4.11 (m, 2H), 2.18 (d, J = 8.4 Hz,1H), 1.78 (d, J = 7.1 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H), 0.75 (d, J =6.9 Hz, 3H). HRMS(B) m/z 413.1732(M + H)+, RT = 2.61 min. 399 & 400:(S)-3-(2-((1-(3- Chiral separation was achieved by chiral SFC columncyclopentyl-1,2,4- chromatography (IA, 5 uM, 20 × 250 mm column, 74oxadiazol-5- ml/min, 99 bar, eluting 15% MeOH/CO2) to give (S)-3-yl)ethyl)amino)pyrimidin-4- (2-(((R)-1-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)-4-isopropyloxazolidin-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- 2-one one and(S)-3-(2-(((S)-1-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one 1st peak399: HRMS(B) m/z 387.2133 (M + H)+. RT = 2.54 min. 2nd peak 400: HRMS(B)m/z 387.2117(M + H)+, RT = 2.50 min. 401 & 402: (S)-3-(2-((1-(3- Chiralseparation was achieved by chiral SFC column cyclohexyl-1,2,4-chromatography (IA, 5 uM, 20 × 250 mm column, 74 oxadiazol-5- ml/min, 99bar, eluting 30% MeOH/CO2) to give (S)-3- yl)ethyl)amino)pyrimidin-4-(2-(((R)-1-(3-cyclohexyl-1,2,4-oxadiazol-5- yl)-4-isopropyloxazolidin-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- 2-one one and(S)-3-(2-(((S)-1-(3-cyclohexyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one 1st peak401: HRMS(B) m/z 401.2277 (M + H)+. RT = 2.71 min. 2nd peak 402: HRMS(B)m/z 401.2288(M + H)+, RT = 2.68 min. 403 & 404: (S)-3-(2-((1-(3- Chiralseparation was achieved by chiral SFC column (tert-butyl)-1,2,4-chromatography (IA, 5 uM, 20 × 250 mm column, 74 oxadiazol-5- ml/min,100 bar, eluting 15% MeOH/CO2) to give (S)-3-yl)ethyl)amino)pyrimidin-4-(2-(((R)-1-(3-(tert-butyl)-1,2,4-oxadiazol-5- yl)-4-isopropyloxazolidin-yl)etnyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- 2-one one and(S)-3-(2-(((S)-1-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one 1st peak403: HRMS(B) m/z 375.2131 (M + H)+. RT = 2.47 min. 2nd peak 404: HRMS(B)m/z375.2130 (M + H)+, RT = 2.44 min. 405 & 406: (S)-3-(2-((1-(3- Chiralseparation was achieved by chiral SFC column isobutyl-1,2,4-oxadiazol-5-chromatography (IA, 5 uM, 20 × 250 mm column, 74yl)ethyl)amino)pyrimidin-4- ml/min, 100 bar, eluting 15% MeOH/CO2) togive (S)-3- yl)-4-isopropyloxazolidin-(2-(((R)-1-(3-isobutyl-1,2,4-oxadiazol-5- 2-oneyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one and(S)-3-(2-(((S)-1-(3-isobutyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one 1st peak405: HRMS(B) m/z 375.2120 (M + H)+. RT = 2.45 min. 2nd peak 406: HRMS(B)m/z 375.2135 (M + H)+, RT = 2.44 min. 407 & 408: (S)-3-(2-((1-(5- Chiralseparation was achieved by chiral SFC column (4-fluorophenyl)-1,3,4-chromatography (IA, 5 uM, 20 × 250 mm column, 74 oxadiazol-2- ml/min, 99bar, eluting 30% IPA/CO2) to give (S)-3-(2- yl)ethyl)amino)pyrimidin-4-(((R)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-4-isopropyloxazolidin-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- 2-one one and(S)-3-(2-(((S)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4- isopropyloxazolidin-2-one1st peak 407: HRMS(B) m/z 413.1713 (M + H)+. RT = 2.31 min. 2nd peak408: HRMS(B) m/z 413.1721 (M + H)+, RT = 2.25 min. 409 & 410:(S)-3-(2-((1- Chiral separation was achieved by chiral SFC column(benzo[d]oxazol-2- chromatography (IA, 5 uM, 20 × 250 mm column, 74yl)ethyl)amino)pyrimidin-4- ml/min, 99 bar, eluting 25% MeOH/CO2) togive (S)-3- yl)-4-isopropyloxazolidin-(2-(((R)-1-(benzo[d]oxazol-2-yl)ethyl)amino)pyrimidin-4- 2-oneyl)-4-isopropyloxazolidin-2-one and (S)-3-(2-(((S)-1-(benzo[d]oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one 1st peak 409: HRMS(B) m/z 368.1729 (M + H)+.RT = 2.66 min. 2nd peak 410: ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.61 (m,1H), 7.54 (s, 1H), 7.51-7.42 (m, 2H), 7.40-7.21 (m, 2H), 6.40 (b, 1H),5.39 (s, 1H), 4.64 (dt, J = 8.1, 3.2 Hz, 1H), 4.36-4.17 (m, 2H), 2.11(b, 1H), 1.77 (d, J = 6.9 Hz, 3H), 0.64 (b, 6H). HRMS(B) m/z 368.1727(M + H)+, RT = 2.60 min. 411 & 412: (S)-3-(2-((1-(4- Separation wasachieved by silica gel chromatography (4-chlorophenyl)-5- (10 to 50%EtOAc/heptane) to give (S)-3-(2-(((R)-1-(4- methylthiazol-2-(4-chlorophenyl)-5-methylthiazol-2- yl)ethyl)amino)pyrimidin-4-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-yl)-4-isopropyloxazolidin- one and(S)-3-(2-(((S)-1-(4-(4-chlorophenyl)-5- 2-onemethylthiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one 1st peak 411: HRMS(B) m/z 458.1401 (M + H)+.RT = 3.02 min. 2nd peak 412: HRMS(B) m/z 458.1401 (M + H)+, RT = 2.92min. 413 & 414: (S)-3-(2-((1-(3- Chiral separation was achieved bychiral SFC column ethyl-1,2,4-oxadiazol-5- chromatography (AD-H column(80 g/min, 80 bar, 20 × yl)ethyl)amino)pyrimidin-4- 250 mm) eluting 15%MeOH/CO2) to give (S)-3-(2- yl)-4-isopropyloxazolidin-(((R)-1-(3-ethyl-1,2,4-oxadiazol-5- 2-oneyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one and(S)-3-(2-(((S)-1-(3-ethyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one 1st peak413: HRMS(B) m/z 346.1753 RT = 2.13 min. 2nd peak 414: HRMS(B) m/z346.1753 RT = 2.05 min. 415 & 416: (S)-4- Chiral separation was achievedby chiral SFC column isopropyl-3-(2-((1-(4- chromatography (AD-H column(75 ml/min, 120 bar, 20 × methylthiazol-2- 250 mm) eluting 10-25%MeOH/CO2) to give (S)-4- yl)ethyl)amino)pyrimidin-4-isopropyl-3-(2-(((R)-1-(4-methylthiazol-2- yl)oxazolidin-2-oneyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-(((S)-1-(4-methylthiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 415: HRMS(B) m/z347.1416 RT = 2.25 min. 2nd peak 416: HRMS(B) m/z 347.1416 RT = 2.17min. 417 & 418: (S)-4- Chiral separation was achieved by chiral SFCcolumn isopropyl-3-(2-((1- chromatography (AD-H column (75 ml/min, 120bar, 20 × (thiophen-2- 250 mm) eluting 10-25% MeOH/CO2) to give (S)-4-yl)ethyl)amino)pyrimidin-4- isopropyl-3-(2-(((R)-1-(thiophen-2-yl)oxazolidin-2-one yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and(S)- 4-isopropyl-3-(2-(((S)-1-(thiophen-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 417: HRMS(B) m/z332.1307 RT = 2.54 min. 2nd peak 418: HRMS(B) m/z 332.1307 RT = 2.53min. 419 & 420: (S)-3-(2-((1- Chiral separation was achieved by chiralSFC column (furan-2- chromatography (AD-H column (75 ml/min, 120 bar, 20× yl)ethyl)amino)pyrimidin-4- 250 mm) eluting 10-25% MeOH/CO2) to give(S)-3- yl)-4-isopropyloxazolidin-(2-(((S)-1-(furan-2-yl)ethyl)amino)pyrimidin-4-yl)-4- 2-oneisopropyloxazolidin-2-one and (S)-3-(2-(((R)-1-(furan-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one 1st peak419: HRMS(B) m/z 316.1535 RT = 2.37 min. 2nd peak 420: HRMS(B) m/z316.1535 RT = 2.39 min. 421 & 422: (S)-4- Chiral separation was achievedby chiral SFC column isopropyl-3-(2-((1-(3- chromatography (IA column(75 ml/min, 120 bar, 20 × (pyridin-4-yl)-1,2,4- 250 mm) eluting 15-25%MeOH/CO2) to give (S)-4- oxadiazol-5-isopropyl-3-(2-(((R)-1-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (S)-yl)oxazolidin-2-one4-isopropyl-3-(2-(((S)-1-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 421: HRMS(B)m/z 395.1706 RT = 1.75 min. 2nd peak 422: HRMS(B) m/z 395.1706 RT = 2.25min. 423 & 424: (S)-3-(2-((1-(3- Chiral separation was achieved bychiral SFC column (2-chlorophenyl)-1,2,4- chromatography (IA column (75ml/min, 120 bar, 20 × oxadiazol-5- 250 mm) eluting 15-25% MeOH/CO2) togive (S)-3-(2- yl)ethyl)amino)pyrimidin-4-(((R)-1-(3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)-4-isopropyloxazolidin-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- 2-one one and(S)-3-(2-(((S)-1-(3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4- isopropyloxazolidin-2-one1st peak 423: HRMS(B) m/z 428.1364 RT = 3.01 min. 2nd peak 424: HRMS(B)m/z 428.1364 RT = 2.79 min. 425 & 426: (S)-3-(2-((1-(3- Chiralseparation was achieved by chiral SFC column (4-chlorophenyl)-1,2,4-chromatography (IA column (75 ml/min, 120 bar, 20 × oxadiazol-5- 250 mm)eluting 15-25% MeOH/CO2) to give (S)-3-(2- yl)ethyl)amino)pyrimidin-4-(((R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-4-isopropyloxazolidin-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- 2-one one and(S)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4- isopropyloxazolidin-2-one1st peak 425: HRMS(B) m/z 428.1364 RT = 2.65 min. 2nd peak 426: ¹H NMR(400 MHz, MeOD) δ 8.22 (d, J = 5.8 Hz, 1.0H), 8.08-7.97 (m, 2.07 H),7.63-7.40 (m, 3.09 H), 5.41 (q, J = 7.2 Hz, 1.04 H), 4.75-4.63 (m, 0.97H), 4.33 (d, J = 6.3 Hz, 2.18 H), 1.76 (d, J = 7.2 Hz, 3.31 H),1.07-0.85 (m, 0.95 H), 0.70 (d, J = 38.0 Hz, 5.81 H). HRMS(B) m/z428.1364 427: (S)-4-isopropyl-3-(2- Chiral separation was achieved bychiral SFC column ((1-(3-(pyridin-3-yl)-1,2,4- chromatography (IA column(75 ml/min, 120 bar, 20 × oxadiazol-5- 250 mm) eluting 15-25% MeOH/CO2)to give (S)-4- yl)ethyl)amino)pyrimidin-4-isopropyl-3-(2-(((R)-1-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)oxazolidin-2-one yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and(S)- 4-isopropyl-3-(2-(((S)-1-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 2nd peak 427: HRMS(B)m/z 395.1706 RT = 2.24 min. 428 & 429: (S)-3-(2-((1-(1- Chiralseparation was achieved by chiral SFC column ethyl-1H-pyrazol-5-chromatography (AD column (75 g/min, 120 bar, 20 ×yl)ethyl)amino)pyrimidin-4- 250 mm) eluting 25% IPA/0.2% DEA/CO2) togive (S)- yl)-4-isopropyloxazolidin- 3-(2-(((R)-1-(1-ethyl-1H-pyrazol-5-2-one yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one and(S)-3-(2-(((S)-1-(1-ethyl-1H-pyrazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- one 1st peak428: HRMS(B) m/z 345.2005 (M + H) RT = 2.28 min. 2nd peak 429: HRMS(B)m/z 345.2044 (M + H) RT = 2.21 min. 430: (S)-4-isopropyl-3-(2- Chiralseparation was achieved by chiral SFC column (((S)-1-(3-(m-tolyl)-1,2,4-chromatography (AD column (75 g/min, 120 bar, 20 × oxadiazol-5- 250 mm)eluting 25-35% IPA/0.2% DEA/CO2) to give yl)ethyl)amino)pyrimidin-4-(S)-4-isopropyl-3-(2-(((R)-1-(3-(m-tolyl)-1,2,4-oxadiazol-yl)oxazolidin-2-one 5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and(S)-4-isopropyl-3-(2-(((S)-1-(3-(m-tolyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 2nd peak 430: HRMS(B)m/z 345.2044 (M + H) RT = 2.82 min. 431 & 432: (S)-4- Chiral separationwas achieved by chiral SFC column isopropyl-3-(2-((1-(2- chromatography(AD column (75 g/min, 120 bar, 20 × phenylthiazol-5- 250 mm) eluting 40%IPA/0.2% DEA/CO2) to give (S)- yl)ethyl)amino)pyrimidin-4-4-isopropyl-3-(2-(((R)-1-(2-phenylthiazol-5- yl)oxazolidin-2-oneyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-(((S)-1-(2-phenylthiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 431: HRMS(B) m/z409.1573 RT = 2.33 min. 2nd peak 432: ¹H NMR (400 MHz, MeOD) δ 8.19 (d,J = 5.8 Hz, 1H), 7.92-7.78 (m, 2H), 7.65 (d, J = 1.1 Hz, 1H), 7.53-7.27(m, 4H), 5.43 (q, J = 6.9 Hz, 1H), 4.74 (dt, J = 7.8, 3.7 Hz, 1H),4.41-4.20 (m, 2H), 2.16 (s, 1H), 1.69 (d, J = 7.0 Hz, 3H), 1.15 (d, J =6.1 Hz, 1H), 0.88-0.49 (m, 6H). HRMS(B) m/z 409.1573 433 & 434: (S)-4-Chiral separation was achieved by chiral SFC columnisopropyl-3-(2-((1-(3-(o- chromatography (AD column (75 g/min, 120 bar,20 × tolyl)-1,2,4-oxadiazol-5- 250 mm) eluting 25-40% IPA/0.2% DEA/CO2)to give yl)ethyl)amino)pyrimidin-4-(S)-4-isopropyl-3-(2-(((R)-1-(3-(o-tolyl)-1,2,4-oxadiazol-yl)oxazolidin-2-one 5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and(S)-4-isopropyl-3-(2-(((S)-1-(3-(o-tolyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 433: HRMS(B)m/z 409.1 (M + H) RT = 2.25 min. 2nd peak 434: ¹H NMR (400 MHz, MeOD) δ8.20 (d, J = 5.8 Hz, 1H), 7.90 (dd, J = 7.7, 1.4 Hz, 1H), 7.47 (d, J =5.8 Hz, 1H), 7.41-7.25 (m, 3H), 5.40 (q, J = 7.2 Hz, 1H), 4.69 (s, 1H),4.44-4.22 (m, 2H), 3.34 (s, 2H), 2.54 (s, 3H), 1.75 (d, J = 7.2 Hz, 3H),1.15 (d, J = 6.1 Hz, 1H), 0.69 (d, J = 35.0 Hz, 6H). HRMS(B) m/z 409.1(M + H) 435 & 436: 4-(1-((4-((S)-4- Chiral separation was achieved bychiral SFC column isopropyl-2-oxooxazolidin- chromatography (AS-H column(80 g/min, 120 bar, 20 × 3-yl)pyrimidin-2- 250 mm) eluting 15% IPA/0.2%DEA/CO2) to give 4- yl)amino)ethyl)-N,N-((R)-1-((4-((S)-4-isopropyl-2-oxooxazolidin-3-dimethylbenzenesulfonamide yl)pyrimidin-2-yl)amino)ethyl)-N,N-dimethylbenzenesulfonamide and 4-((S)-1-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)-N,N-dimethylbenzenesulfonamide 1st peak 435: HRMS(B) m/z433.1784 RT = 2.45 min. 2nd peak 436: HRMS(B) m/z 433.1784 RT = 2.32min. 437 & 438: (S)-4- Chiral separation was achieved by chiral SFCcolumn isopropyl-3-(2-((1-(thiazol- chromatography (IC column (75 g/min,120 bar, 20 × 4-yl)ethyl)amino)pyrimidin- 250 mm) eluting 25% IPA/0.2%DEA/CO2) to give (S)- 4-yl)oxazolidin-2-one4-isopropyl-3-(2-(((S)-1-(thiazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-(((R)-1-(thiazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 437: HRMS(B) m/z333.1259 RT = 1.88 min. 2nd peak 438: HRMS(B) m/z 333.1259 RT = 1.98min. 439 & 440: (S)-4- Chiral separation was achieved by chiral SFCcolumn isopropyl-3-(2-((1-(3-(4- chromatography (Al column (70 g/min,120 bar, 20 × methoxyphenyl)-1,2,4- 250 mm) eluting 20% IPA/0.2%DEA/CO2) to give (S)- oxadiazol-5-4-isopropyl-3-(2-(((R)-1-(3-(4-methoxyphenyl)-1,2,4-yl)ethyl)amino)pyrimidin-4-oxadiazol-5-yl)etnyl)amino)pyrimidin-4-yl)oxazolidin-2-yl)oxazolidin-2-one one and (S)-4-isopropyl-3-(2-(((S)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 1st peak 438: HRMS(B) m/z425.1921 (M + H) RT = 2.49 min. 2nd peak 439: HRMS(B) m/z 425.1923 (M +H) RT = 2.42 min. 441 & 442: (S)-3-(2-((1-(3- Chiral separation wasachieved by chiral SFC column (4-fluorophenyl)-1,2,4- chromatography (Alcolumn (70 g/min, 120 bar, 20 × oxadiazol-5- 250 mm) eluting 25%IPA/0.2% DEA/CO2) to give (S)- yl)ethyl)amino)pyrimidin-4-3-(2-(((R)-1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-4-isopropyloxazolidin-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- 2-one one and(S)-3-(2-(((S)-1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4- isopropyloxazolidin-2-one1st peak 441: HRMS(B) m/z 413.1719 (M + H) RT = 2.58 min. 2nd peak 442:HRMS(B) m/z 413.1719 (M + H) RT = 2.52 min. 443: (S)-3-(2-(((S)-1-(5-(4-Chiral separation was achieved by chiral SFC column chlorophenyl)-1,2,4-chromatography (ID-H column (80 g/min, 120 bar, 20 × oxadiazol-3- 250mm) eluting 30% MeOH/CO2) to give (S)-3-(2- yl)ethyl)amino)pyrimidin-4-(((R)-1-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)-4-isopropyloxazolidin-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2- 2-one one and(S)-3-(2-(((S)-1-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4- isopropyloxazolidin-2-one2nd peak 443: ¹H NMR (400 MHz, MeOD) δ 8.25-8.03 (m, 6H), 7.71-7.55 (m,4H), 7.44 (d, J = 5.7 Hz, 2H), 5.26 (d, J = 5.6 Hz, 2H), 4.71 (d, J =7.9 Hz, 2H), 4.46- 4.26 (m, 4H), 3.37 (s, 1H), 2.66 (heptd, J = 7.0, 3.3Hz, 2H), 1.69 (d, J = 7.1 Hz, 6H), 1.17 (d, J = 6.2 Hz, 1H), 1.04 (d, J= 7.1 Hz, 6H), 0.88 (d, J = 6.9 Hz, 6H). HRMS(B) m/z 428.1364 RT = 2.77min. 444 & 445: (S)-3-(2-(1-(5- Separation was achieved by silica gelchromatography (4-fluoro-3- (10 to 100% EtOAc/heptane) to give(S)-3-(2-((R)-1- methylphenyl)pyridin-2-(5-(4-fluoro-3-methylphenyl)pyridin-2- yl)ethylamino)pyrimidin-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-yl)-4-isopropyloxazolidin- one and (S)-3-(2-((S)-1-(5-(4-fluoro-3- 2-onemethylphenyl)pyridin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one 1st peak 444: HRMS(B) m/z 436.2126 (M + H)+,RT = 2.78 min 2nd peak 445: ¹H NMR (400 MHz, CDCl₃) δ 8.75 (dd, J = 2.3,0.9 Hz, 1H), 8.23 (d, J = 5.8 Hz, 1H), 7.78 (dd, J = 8.1, 2.4 Hz, 1H),7.49 (d, J = 5.7 Hz, 1H), 7.41-7.27 (m, 3H), 7.12 (dd, J = 9.4, 8.4 Hz,1H), 5.95 (d, J = 6.5 Hz, 1H), 5.16 (br s, 1H), 4.66 (br s, 1H),4.34-4.19 (m, 2H), 2.37 (d, J = 1.9 Hz, 3H), 1.93 (br s, 1H), 1.65- 1.61(m, 3H), 0.71 (br s, 6H). HRMS(B) m/z 436.2131 (M + H)+. 446 & 447:(S)-3-(2-(1-(5- Chiral separation was achieved by chiral SFC column (4-chromatography (Column IA 20 × 250 mm column 30%fluorophenoxy)pyrimidin- IPA, 70% CO2) to give (S)-3-(2-((S)-1-(5-(4-2-yl)ethylamino)pyrimidin-fluorophenoxy)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)- 4-yl)-4-4-isopropyloxazolidin-2-one and (S)-3-(2-((R)-1-(5-(4-isopropyloxazolidin-2-onefluorophenoxy)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one 1st peak 446: ¹H NMR (400 MHz, CDCl₃) δ 8.42(s, 2H), 8.21 (d, J = 5.8 Hz, 1H), 7.49 (d, J = 5.7 Hz, 1H), 7.18- 6.99(m, 4H), 6.18 (br s 1H), 5.28 (br s, 1H), 4.75 (dt, J = 8.2, 3.4 Hz,1H), 4.39-4.25 (m, 2H), 2.34 (br s, 1H), 1.65-1.59 (m, 3H), 0.95-0.86(d, J = 6.9 Hz, 3H), 0.82 (d, J = 6.9 Hz, 3H). HRMS(B) m/z 439.1876 (M +H)+. 2nd peak 447: HRMS(B) m/z 439.1883 (M + H)+, RT = 3.37 min 448 &449: (S)-3-(2-(1-(5- Separation was achieved by silica gelchromatography (4-fluorophenoxy)pyridin- (20 to 100% EtOAc/heptane) togive (S)-3-(2-((R)-1-(5- 2-yl)ethylamino)pyrimidin-(4-fluorophenoxy)pyridin-2-yl)ethylamino)pyrimidin-4-yl)- 4-yl)-4-4-isopropyloxazolidin-2-one and (S)-3-(2-((S)-1-(5-(4-isopropyloxazolidin-2-onefluorophenoxy)pyridin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one 1st peak 448: HRMS(B) m/z 438.1922 (M + H)+.RT = 2.62 min 2nd peak 449: ¹H NMR (400 MHz, CDCl₃) δ 8.34 (dd, J = 2.7,0.8 Hz, 1H), 8.21 (d, J = 5.8 Hz, 1H), 7.49 (d, J = 5.8 Hz, 1H),7.33-7.18 (m, 3H), 7.14-6.95 (m, 3H), 5.95 (d, J = 7.1 Hz, 1H), 5.14 (brs, 1H), 4.68 (d, J = 7.8 Hz, 1H), 4.36-4.22 (m, 2H), 1.75 (br s, 1H),1.61- 1.57 (m, 3H), 0.95-0.75 (m, 6H). HRMS(B) m/z 438.1950 (M + H)+.450 & 451: (R)-3-(5- Separation was achieved by silica gelchromatography fluoro-2-(1-(5-(4- (10 to 100% EtOAc/heptane) to give(R)-3-(5-fluoro-2- fluorophenoxy)pyridin-2-((S)-1-(5-(4-fluorophenoxy)pyridin-2- yl)ethylamino)pyrimidin-4-yl)ethylamino)pyrimidin-4-yl)-5,5-dimethyl-4- yl)-5,5-dimethyl-4-phenyloxazolidin-2-one and (R)-3-(5-fluoro-2-((R)-1-(5-phenyloxazolidin-2-one(4-fluorophenoxy)pyridin-2-yl)ethylamino)pyrimidin-4-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one 1st peak 450: ¹H NMR (400 MHz,CDCl₃) δ 8.27-8.17 (m, 1H), 8.08 (d, J = 2.8 Hz, 1H), 7.31-6.86 (m,11H), 5.83 (d, J = 7.2 Hz, 1H), 5.28 (s, 1H), 4.69 (br s, 1H), 1.58 (s,3H), 1.29-1.11 (m, 3H), 0.98 (s, 3H). HRMS(B) m/z 518.2005 (M + H)+. 2ndpeak 451: HRMS(B) m/z 518.2003 (M + H)+, RT = 3.08 min 452 & 453:(S)-3-(2-(1-(5- Separation was achieved by silica gel chromatography(4-fluorophenoxy)pyrazin- (25 to 100% EtOAc/heptane) to give(S)-3-(2-((R)-1- 2-yl)ethylamino)pyrimidin-(5-(4-fluorophenoxy)pyrazin-2-yl)ethylamino)pyrimidin- 4-yl)-4-4-yl)-4-isopropyloxazolidin-2-one and (S)-3-(2-((S)-1-(5-isopropyloxazolidin-2-one.(4-fluoropnenoxy)pyrazin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one. 1st peak 452: HRMS(B) m/z 439.1877 (M +H)+, RT = 2.66 min 2nd peak 453: ¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, J =1.4 Hz, 1H), 8.20 (d, J = 5.8 Hz, 1H), 8.09 (s, 1H), 7.49 (d, J = 5.8Hz, 1H), 7.12 (d, J = 6.3 Hz, 4H), 5.71 (s, 1H), 5.20 (br s, 1H), 4.66(dt, J = 7.7, 2.9 Hz, 1H), 4.36- 4.22 (m,2H), 2.10 (br s, 1H), 1.61 (d,J = 6.9 Hz, 3H), 0.94-0.78 (m, 6H). HRMS(B) m/z 439.1882 (M + H)+. 454 &455: (S)-3-(2-(1-(2- Separation was achieved by silica gelchromatography (4- (25 to 100% EtOAc/heptane) to give(S)-3-(2-((R)-1-(2- fluorophenoxy)pyrimidin-(4-fluorophenoxy)pyrimidin-5-yl)ethylamino)pyrimidin-4-5-yl)ethylamino)pyrimidin- yl)-4-isopropyloxazolidin-2-one and(S)-3-(2-((S)-1-(2- 4-yl)-4-(4-fluorophenoxy)pyrimidin-5-yl)ethylamino)pyrimidin-4-isopropyloxazolidin-2-one. yl)-4-isopropyloxazolidin-2-one. 1st peak454: HRMS(B) m/z 439.1904 (M + H)+, RT = 3.09 min 2nd peak 455: HRMS(B)m/z 439.1897 (M + H)+, RT = 3.17 min 456: (S)-3-(2-(1-(5-(2,4-Separation was achieved on a normal phase silica geldifluorophenoxy)pyrimidin- column with 20 to 100% ethylacetate/heptaneto give 2-yl)ethylamino)pyrimidin-(S)-3-(2-((R)-1-(5-(2,4-difluorophenoxy)pyrimidin-2- 4-yl)-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-isopropyloxazolidin-2-one. one and (S)-3-(2-((S)-1-(5-(2,4-difluorophenoxy)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one. 2^(nd) Peak 456: ¹H NMR (400 MHz,CDCl₃) δ 8.30 (s, 2H), 8.09 (d, J = 5.9 Hz, 1H), 7.42 (d, J = 5.9 Hz,1H), 7.08 (td, J = 8.9, 5.4 Hz, 1H), 6.98-6.81 (m, 2H), 5.18 (br s, 1H),4.64 (dt, J = 7.9, 3.1 Hz, 1H), 4.30-4.16 (m, 2H), 2.11 (br s, 1H),1.53-1.49 (m, 3H), 0.85-0.77 (m, 3H), 0.71 (d, J = 6.8 Hz, 3H). HRMS(B)m/z 457.1797 (M + H)+. 457: (S)-4-isopropyl-3-(2- Separation wasachieved on a normal phase silica gel (1-(5-(3- column with 25 to 100%gradient of (25% methanol in (trifluoromethyl)phe- ethylacetate) andheptane to give (S)-4-isopropyl-3-(2- nyl)pyrimidin-2-((R)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4- yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-oneand (S)-4- yl)oxazolidin-2-one. isopropyl-3-(2-((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one. Peak 2 457: ¹H NMR (400MHz, CDCl₃) δ 8.85 (s, 2H), 8.14 (d, J = 5.7 Hz, 1H), 7.77-7.54 (m, 4H),7.40 (d, J = 5.7 Hz, 1H), 6.11 (br s, 1H), 5.25 (br s, 1H), 4.67 (dt, J= 7.8, 3.2 Hz, 1H), 4.33-4.15 (m, 2H), 2.92 2.15 (br s, 1H), 1.55 (d, J= 8.6 Hz, 3H), 0.85-0.76 (m, 3H), 0.70 (br s, 3H). HRMS(B) m/z 473.1897(M + H)+. 458: (S)-3-(2-((S)-1-(5-(4- The chiral separation was carriedout with SFC (IA, fluoro-2- 5 μm, 20 × 250 mm) using 35% MeOH in CO2 togive methylphenyl)pyrimidin-2-(S)-3-(2-((S)-1-(5-(4-fluoro-2-methylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-yl)-4-isopropyloxazolidin- one and (S)-3-(2-((R)-1-(5-(4-fluoro-2- 2-onemethylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one 1st Peak 458: ¹H NMR (400 MHz, CDCl₃) δ 8.68(s, 2H), 8.24 (d, J = 5.8 Hz, 1H), 7.49 (d, J = 5.7 Hz, 1H), 7.17 (dd, J= 8.4, 5.8 Hz, 1H), 7.10-6.98 (m, 2H), 6.28 (br s, 1H), 5.34 (br s, 1H),4.78 (dt, J = 8.2, 3.3 Hz, 1H), 4.40- 4.25 (m, 2H), 2.30 (s, 3H), 1.79(br s, 1H), 1.73 (d, J = 7.1 Hz, 3H), 0.95-0.75 (m, 6H). HRMS(B) m/z437.2086 (M + H)+.

Example 459

A solution of (S)-(4-(1-aminoethyl)phenyl)methanol hydrochloride (4.0301g, 21.47 mmol, purchased from NetChem),(S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (5.3648 g,23.82 mmol, 1.11 equiv) and DIPEA (38.0 mL, 218 mmol, 10.1 equiv) inDMSO (40 mL) was heated at 110° C. for 135 min. The reaction mixture wasdiluted with EtOAc (200 mL) and washed with water (200 mL). Afterseparation, the aqueous phase was washed with EtOAc (2×150 mL). Combinedorganics were dried over Na₂SO₄, filtered and concentrated. Silica gelcolumn chromatography (EtOAc/heptane 30 to 100%) provided(S)-3-(2-((S)-1-(4-(hydroxymethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one(6.42 g) in 84% yield. ¹H NMR (400 MHz, CD₃OD) δ 8.13 (d, J=5.8 Hz, 1H),7.36-7.28 (m, 5H), 5.06 (q, J=7.0 Hz, 1H), 4.68 (br s, 1H), 4.58 (s,2H), 4.37-4.29 (m, 2H), 1.80 (br s, 1H), 1.52 (d, J=7.1 Hz, 3H), 0.74(br s, 3H), 0.61 (br s, 3H); MS m/z 355.1 (M−H)

Example 460

S)-3-(2-((S)-1-(3-fluoro-4-(hydroxymethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-onewas prepared using a method similar to that described for thepreparation of Example 459. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=5.9 Hz,1H), 7.51-7.49 (m, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H),7.01 (d, J=11, Hz, 1H), 6.09 (br s, 1H), 5.00 (br s, 1H), 4.73 (s, 2H),4.61-4.55 (m, 1H), 4.30 (t, J=8.7 Hz, 1H), 4.25-4.21 (m, 1H), 3.00 (s,1H), 1.89 (br s, 1H), 1.54 (d, J=7.1 Hz, 3H), 0.67 (br s, 6H); MS m/z375.0 (M+H)

Example 461

A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(50 mg, 0.165 mmol), 2,2,2-trifluoro-1-phenylethanamine (160 mg, 0.913mmol) and pTsOH (78 mg, 0.412 mmol) in 2-BuOH was heated at 110° C. for2.5 h. LCMS shows starting material as well as product. Another 78 mg ofpTsOH was added followed by 98 mg of 2,2,2-trifluoro-1-phenylethanamineand heated at 110 C for 1.5 h. Mostly product some SM.

After cooling down mixture solidified. Added acetonitrial and sonicated.Filtered off solids (pTsOH salt of 2,2,2-trifluoro-1-phenylethanamine).The mother liquor was concentrated and purified by column chromatography(0-40% EtOAc/Hept followed by reverse HPLC (XBridge C18 5 uM 10-85%ACN/Water over 12 minutes with 0.01% NH4OH modifier) to give(4R)-5,5-dimethyl-4-phenyl-3-(2-(2,2,2-trifluoro-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one(28 mg, 0.063 mmol).

¹H NMR (400 MHz, MeOD) δ 8.20 (d, J=5.8 Hz, 1H), 7.58 (dd, J=11.4, 5.8Hz, 1H), 7.51 (br d, J=6.8 Hz, 1H), 7.40 (dtd, J=15.9, 9.2, 4.5 Hz, 5H),7.33-7.22 (m, 3H), 7.10 (br s, 1H), 5.50 (s, 0.5H), 5.38 (s, 0.5H), 5.29(br s, 1H), 1.70 (s, 1.5H), 1.64 (s, 1.5H), 1.04 (s, 1.5H), 1.03 (s,1.5H). HRMS(B) (M+H) 443.1682 Calc'd (M+H) 443.1695

Example 462 & 463

A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(163 mg, 0.674 mmol), 2,2,2-trifluoro-1-phenylethanamine (624 mg, 3.56mmol, 5.3 equiv) and p-toluenesulfonic acid monohydrate (321 mg, 1.69mmol, 2.5 equiv) in n-BuOH (3 mL) was heated at 110° C. for 2 h andtreated with additional p-toluenesulfonic acid monohydrate (321 mg, 1.69mmol, 2.5 equiv), then heated at 110° C. for 1½ h. After cooling, thesolid reaction mixture was treated with MeCN, sonicated and filtered.The filtrated was concentrated and purified by silica gel columnchromatography (EtOAc/Heptane 0 to 30%) to give(4S)-4-isopropyl-3-(2-(2,2,2-trifluoro-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one(65 mg) in 25% yield. HRMS(B) m/z 381.1545 (M+H)+. Anal. RP-HPLCtR=4.31//4.46 min (1.0 mL/min flow rate with gradient from 5% to 15%acetonitrile with 0.05% formic acid in 5.00 min and then 15% to 95%acetonitrile with 0.05% formic acid from 5.00 min to 9.50 min, aqueousphase modified with 0.1% formic acid. Silica gel column chromatographyseparated the two diastereomers(S)-4-isopropyl-3-(2-((R)-2,2,2-trifluoro-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-oneand(S)-4-isopropyl-3-(2-((S)-2,2,2-trifluoro-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one.

1^(st) Peak: ¹H NMR (400 MHz, MeOD) δ 8.23 (d, J=5.8 Hz, 1H), 7.62-7.53(m, 2H), 7.50 (d, J=5.8 Hz, 1H), 7.42 (qt, J=5.0, 2.2 Hz, 3H), 5.93-5.86(m, 1H), 4.80 (dt, J=7.5, 3.9 Hz, 1H), 4.48-4.33 (m, 2H), 2.65 (ddp,J=10.4, 7.0, 3.4 Hz, 1H), 1.05 (d, J=7.0 Hz, 3H), 0.89 (d, J=7.0 Hz,3H).

2^(nd) Peak: ¹H NMR (400 MHz, MeOD) δ 8.23 (d, J=5.8 Hz, 1H), 7.55 (dd,J=7.3, 2.1 Hz, 2H), 7.49 (d, J=5.8 Hz, 1H), 7.45-7.32 (m, 3H), 5.92-5.86(m, 1H), 4.86-4.82 (m, 1H), 4.44-4.38 (m, 2H), 2.26 (br s, 1H), 0.94 (d,J=7.0 Hz, 3H), 0.74 (br s, 3H).

Example 464

A solution of (S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(1055 mg, 4.68 mmol),1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethanamine (1300 mg, 5.62mmol, 1.2 equiv) and diisopropylethylamine (908 mg, 7.03 mmol, 1.5equiv) in DMSO (20 mL) was heated at 110° C. for 1 h. The reactionmixture was poured into water (60 mL) and extracted with EtOAc (2×50mL). Combined organics were washed with water (40 mL), brine (40 mL),dried over Na₂SO₄, filtered and concentrated directly onto silica gel.Silica gel chromatography provided the mixed distereomers of(S)-3-(2-(1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (560 mg). Chiral separationwas carried out with SFC (ID, 5 μm, 20×250 mm) using 35% MeOH in CO2 togive(S)-3-(2-((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneand(S)-3-(2-((R)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.

Example 464 first eluted product (302 mg)¹H NMR (400 MHz, CDCl₃) δ 8.87(s, 2H), 8.23 (d, J=5.8 Hz, 1H), 7.49 (d, J=5.7 Hz, 1H), 7.43-7.30 (m,2H), 7.21-7.11 (m, 1H), 6.26 (br s, 1H), 5.31 (br s, 1H), 4.75 (dt,J=7.9, 3.3 Hz, 1H), 4.39-4.24 (m, 2H), 2.38 (s, 3H), 2.09 (br s, 1H),1.66-1.62 (m, 3H), 0.90 (dd, J=9.8, 6.0 Hz, 3H), 0.78 (br s, 3H).HRMS(B) m/z 437.2093 (M+H)+.

Example 465

A solution of(S)-4-isopropyl-3-(2-((S)-1-(piperidin-4-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one(225 mg, 0.675 mmol), 4-fluorobenzene-1-sulfonyl chloride (146 mg, 0.750mmol) and DIPEA (1 ml) in CH₂Cl₂ was stirred at room temperature for 2h. The reaction mixture was diluted with CH₂Cl₂ and washed with water.Aqueous layer was extracted with CH₂Cl₂. Combined organics were washedwith brine, dried over Na₂SO₄, filtered and concentrated. The residuewas purified by column chromatography to give(S)-3-(2-((S)-1-(1-(4-fluorophenylsulfonyl)piperidin-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one(4.5 mg, 0.009 mmol).

¹H NMR (400 MHz, MeOD) δ 8.45 (d, J=6.0 Hz, 1H), 8.23-8.15 (m, 2H),7.73-7.63 (m, 3H), 5.13 (dt, J=7.4, 3.7 Hz, 1H), 4.78-4.69 (m, 2H), 4.26(p, J=6.7 Hz, 1H), 4.17 (dddd, J=11.8, 6.4, 4.7, 2.3 Hz, 2H), 2.89 (ddq,J=10.7, 7.1, 3.5 Hz, 1H), 2.69 (tdd, J=11.6, 8.9, 2.6 Hz, 2H), 2.27-2.11(m, 2H), 1.82 (dddt, J=11.9, 9.0, 5.8, 2.9 Hz, 1H), 1.77-1.64 (m, 2H),1.52 (d, J=6.8 Hz, 3H), 1.30 (d, J=7.1 Hz, 3H), 1.21 (d, J=6.9 Hz, 3H).HRMS(B) (M+H) 492.2069 Calc'd (M+H) 492.2081

The following examples were prepared using methods substantially similarto those described for Example 465:

Example 466

Purified by column chromatography (20% to 100% EtOAc/Hept), followed byreverse phase preparative chromatography (C18 column, 10-85% ACN/Water0.1% NH4OH modifier over 12 min.) to give(S)-3-(2-((S)-1-(1-(4-fluorobenzoyl)piperidin-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one(12 mg, 0.026 mmol).

¹H NMR (400 MHz, MeOD) δ 8.12 (d, J=5.8 Hz, 1H), 7.51-7.41 (m, 2H), 7.36(d, J=5.8 Hz, 1H), 7.25-7.15 (m, 2H), 4.82 (td, J=5.9, 3.6 Hz, 1H), 4.68(br s, 1H), 4.41 (d, J=5.7 Hz, 2H), 3.98 (p, J=6.7 Hz, 1H), 3.78 (br s,1H), 3.12 (br s, 1H), 2.82 (br s, 1H), 2.60 (pd, J=7.1, 6.5, 3.7 Hz,1H), 1.92 (br s, 1H), 1.80 (dtd, J=15.3, 9.4, 7.0, 3.6 Hz, 2H), 1.31 (brs, 2H), 1.22 (d, J=6.8 Hz, 3H), 0.99 (d, J=7.1 Hz, 3H), 0.88 (d, J=6.9Hz, 3H). HRMS(B) (M+H) 456.2384 Calc'd (M+H) 456.2411

Example 467

Purified by column chromatography (MeOH/CH₂Cl₂ 0 to 20%) to give(S)-4-isopropyl-3-(2-((S)-1-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one(15 mg, 0.034 mmol).

¹H NMR (400 MHz, MeOD) δ 8.12 (d, J=5.8 Hz, 1H), 7.36 (d, J=5.8 Hz, 1H),4.81 (td, J=5.6, 3.3 Hz, 1H), 4.59 (br s, 1H), 4.41 (d, J=5.7 Hz, 2H),4.13 (br s, 1H), 3.96 (ddd, J=11.6, 4.3, 2.2 Hz, 3H), 3.51 (tq, J=11.8,2.8 Hz, 2H), 3.15-2.89 (m, 2H), 2.69-2.48 (m, 2H), 1.99-1.68 (m, 5H),1.61 (ddt, J=10.7, 4.0, 2.3 Hz, 2H), 1.35-1.23 (m, 1H), 1.21 (d, J=6.7Hz, 3H), 1.19-1.09 (m, 1H), 0.98 (dd, J=7.0, 1.5 Hz, 3H), 0.88 (d, J=7.0Hz, 3H). HRMS(B) (M+H) 446.2748 Calc'd (M+H) 446.2767

Example 468

Purified by column chromatography (50% to 100% EtOAc/Heptane followed by0% to 20% MeOH/CH₂Cl₂) to give(S)-4-isopropyl-3-(2-((S)-1-(1-(morpholine-4-carbonyl)piperidin-4-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one(21 mg, 0.047 mmol).

¹H NMR (400 MHz, MeOD) δ 8.11 (d, J=5.8 Hz, 1H), 7.36 (d, J=5.8 Hz, 1H),4.81 (td, J=5.8, 3.4 Hz, 1H), 4.41 (d, J=5.7 Hz, 2H), 3.95 (p, J=6.8 Hz,1H), 3.84-3.70 (m, 2H), 3.68-3.65 (m, 4H), 3.26-3.23 (m, 4H), 2.80 (tt,J=12.9, 3.1 Hz, 2H), 2.60 (ddq, J=10.4, 7.0, 3.5 Hz, 1H), 1.88-1.73 (m,2H), 1.67 (ddt, J=18.5, 10.4, 3.5 Hz, 1H), 1.37-1.23 (m, 2H), 1.21 (d,J=6.8 Hz, 3H), 0.99 (d, J=7.1 Hz, 3H), 0.88 (d, J=7.0 Hz, 3H). HRMS(B)(M+H) 447.2690 Calc'd (M+H) 447.2720

Example 469

Purified by column chromatography to give(S)-3-(2-((S)-1-(1-(cyclohexanecarbonyl)piperidin-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

¹H NMR (400 MHz, MeOD) δ 8.12 (d, J=5.7 Hz, 1H), 7.36 (d, J=5.6 Hz, 1H),4.80 (dt, J=5.8, 2.9 Hz, 1H), 4.59 (br s, 1H), 4.40 (d, J=5.6 Hz, 2H),4.18-4.03 (m, 1H), 3.95 (p, J=6.8 Hz, 1H), 3.05 (ddd, J=14.1, 10.1, 6.6Hz, 1H), 2.58 (td, J=25.1, 23.5, 13.0 Hz, 3H), 1.97-1.63 (m, 8H),1.54-1.08 (m, 7H), 1.21 (d, J=6.8 Hz, 3H), 0.98 (d, J=6.8 Hz, 3H), 0.88(d, J=6.9 Hz, 3H). HRMS(B) (M+H) 444.2953 Calc'd (M+H) 444.2975

Examples 470

A solution of(S)-3-(2-(((S)-1-(4-aminophenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one(100 mg, 0.30 mmol), benzenesulfonyl chloride (65 mg, 0.36 mmol, 1.2equiv) and pyridine (35 mg, 0.45 mmol, 1.5 equiv) in DCM (5 mL) wasstirred at room temperature for 15 h. The reaction mixture was quenchedwith MeOH, the solvent was removed to yield the crude product, which waspurified by silica gel column chromatography (EA:MeOH=1:0 to 9:1), thesolvent was removed to afford the pure product (46.8 mg, white solid) ina 31.5% yield.N-(4-((S)-1-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)phenyl)benzenesulfonamide.¹H NMR (400 MHz, CDCl₃) δ 8.18-7.90 (m, 2H), 7.74 (d, J=7.8 Hz, 2H),7.45 (t, J=7.4 Hz, 1H), 7.39-7.35 (m, 2H), 7.10 (d, J=8.1 Hz, 2H), 6.96(d, J=8.0 Hz, 2H), 6.41 (s, 1H), 4.99-4.79 (m, 1H), 4.62-4.39 (m, 1H),4.28-3.99 (m, 2H), 1.91-1.65 (b, 1H), 1.40 (d, J=7.0 Hz, 3H), 0.53 (b,J=21.1 Hz, 6H). HRMS(B) m/z 482.1847 (M+H)⁺. RT=2.60 min.

Examples 471

A solution of (triethoxymethyl)benzene (360 mg, 1.6 mmol, 5.0 equiv. in5 mL of benzene and 0.5 mL of glacial AcOH) was added to(S)-2-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)propanehydrazide(99 mg, 0.30 mmol, 1.0 equiv.), the reaction mixture was stirred atreflux for 1.5 hours, the solvent was removed to yield the crudeproduct. Silica gel column chromatography (ethyl acetate in heptane 10to 90%) to yield(S)-4-isopropyl-3-(2-(((S)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(21.2 mg, white solid) in 15.9% yield. HRMS(B) m/z 395.1820, (M+H)+,RT=2.42 min

Examples 472

To a solution of(S)-4-isopropyl-3-(2-(((S)-1-(5-(methylthio)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(102 mg, 0.28 mmol in 1.5 ml of CH₃COOH), was added a solution of KMnO₄(66.4 mg, 0.42 mmol, 1.5 eq in 2.5 ml of water) dropwise. The solutionwas stirred at room temperature for 25 min, the mixture was decolorizedwith sodium bisulfite, the resulting solution was extracted with DCM,washed with sat. NaHCO₃, dried over Na₂SO₄, the solvent was removed toyield the pure desired product as a white solid.(S)-4-isopropyl-3-(2-(((S)-1-(5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(83 mg, white solid) in 71% yield. HRMS(B) m/z 397.1281 (M+H)⁺. RT=1.80min.

Example 473 & 474

1-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-ethanone (75 mg, 0.468 mmol), ammoniumacetate (722 mg, 9.36 mmol, 20.0 eq) and sodium cyanoborodeuteride (131mg, 1.999 mmol, 4.25 eq) were combined in propan-2-ol (5 ml) and heatedunder infrared irradiation at 130° C. for 4 min. The reaction wasdiluted with EtOAc (15 ml) and water (15 ml) and treated with 6M NaOHsolution (1 ml) to ˜10 pH. The product,1-deutero-1-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethanamine, was carried tothe next step without further purification.

A solution of 3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (99 mg, 0.441mmol), 1-deutero-1-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethanamine (72 mg,0.441 mmol, 1.0 equiv), and DIEA (0.154 mL, 0.882 mmol, 2.0 equiv) inDMSO (1 mL) was heated at 130° C. for 120 min. The reaction mixture wasdiluted with EtOAc (20 mL) and washed with water (10 mL) andconcentrated in vacuo. Resolution of(4S)-3-(2-((1-deutero-1-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-onevia chiral SFC chromatography on a Al column (75 g/min, 120 bar, 20×250mm) eluting 40-50% MeOH/0.2% DEA/CO2 (v/v) to give(4S)-3-(2-(((R)-1-deutero-1-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneand(4S)-3-(2-(((S)-1-deutero-1-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

1st Peak 473

¹H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 8.33 (d, J=2.2 Hz, 1H), 8.21(d, J=5.7 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H), 7.46 (d, J=5.7 Hz, 1H), 7.35(dd, J=3.5, 2.0 Hz, 1H), 6.47 (dd, J=3.4, 1.7 Hz, 1H), 5.82 (s, 1H),1.66-1.58 (m, 3H), 4.59 (dt, J=7.7, 3.2 Hz, 1H), 4.28 (t, J=8.8 Hz, 1H),4.19 (dd, J=9.2, 3.1 Hz, 1H), 3.51 (s, 1H), 1.78 (d, J=28.5 Hz, 2H),1.30-1.15 (m, 1H), 0.57 (s, 6H). LCMS m/z 368.1 (M+H) RT=2.36 min.

2nd Peak 474

LCMS m/z 368.1 (M+H) RT=2.66 min.

Example 475

A solution of 3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (100 mg, 0.444mmol), (3-(p-tolyl)-1,2,4-oxadiazol-5-yl)methanamine (84 mg, 0.444 mmol,1.0 equiv), and TEA (0.186 mL, 1.332 mmol, 3.0 equiv) in butan-1-ol (2mL) was heated at 100° C. for 90 min. Addition of propan-1-ol (1 ml) andheated at 150° C. for 60 min. The reaction mixture was concentrated invacuo. Flash column (silica, 24 g) eluting w/0-30% EtOAc/DCM afforded(S)-4-Isopropyl-3-{2-[(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amino]-pyrimidin-4-yl}-oxazolidin-2-one(95 mg, white foam) in 54.2% yield. HRMS(B) m/z 394.1753 2.38 Min.

Example 476

To a solution of4-{(S)-1-[4-((S)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-pyrimidin-2-ylamino]-ethyl}-piperidine-1-carboxylicacid benzyl ester (22 mg) in methanol (5 mL) was added palladiumhydroxide on carbon (7 mg, 0.05 mmol). The reaction was then stirred atroom temperature for 16 hours. The reaction is then filtered and thenconcentrated under vacuum. The crude material was then purified usingreverse phase C18 ODB column water-acetonitrile 0.1% TFA modifier togive(S)-4-isopropyl-3-[2-((S)-1-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-oxazolidin-2-one(11 mg) in 70% yield.

HRMS(B) m/z 333.2165 (M+H)+; RT.: 1.09 min.

Example 477

A solution of(S)-4-Isopropyl-3-[2-((S)-1-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-oxazolidin-2-one(28 mg, 0.084 mmol) in THF (2 mL) was added cyclobutanone (14 mg, 0.20mmol) and sodium triacetoxyborohydride (28 mg, 0.13 mmol). The reactionwas stirred at room temperature for 18 hours. The solvent is thenremoved under vacuum. The crude material was then purified using reversephase C18 ODB column water-acetonitrile 0.1% TFA modifier to give(S)-3-{2-[(S)-1-(1-Cyclobutyl-piperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-4-isopropyl-oxazolidin-2-one(20 mg) in 62% yield.

HRMS(B) m/z 388.2717 (M+H)+; RT.: 2.32 min.

Example 478

A solution of(S)-4-Isopropyl-3-[2-((S)-1-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-oxazolidin-2-one(20 mg, 0.060 mmol) in THF (2 mL) was added cyclobutanone (10 mg, 0.17mmol) and sodium triacetoxyborohydride (20 mg, 0.09 mmol). The reactionwas stirred at room temperature for 18 hours. The solvent is thenremoved under vacuum. The crude material was then purified using reversephase C18 ODB column water-acetonitrile 0.1% TFA modifier to give(S)-4-Isopropyl-3-{2-[(S)-1-(1-isopropyl-piperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-oxazolidin-2-one(20 mg) in 62% yield.

HRMS(B) m/z 376.2705 (M+H)+; RT.: 1.24 min.

Example 479

To a solution ofS)-4-Isopropyl-3-[2-((S)-1-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-oxazolidin-2-one(20 mg, 0.48 mmol) in dichloromethane (1 mL) and DMF (1 mL) was addedHATU (23 mg, 0.06 mmol) and DIPEA (0.03 mL, 0.18 mmol) The reaction wasstirred at room temperature for 18 hours. The solvent is then removedunder vacuum. The crude material was then purified using reverse phaseC18 ODB column water-acetonitrile 0.1% TFA modifier to give(S)-4-Isopropyl-3-(2-{(S)-1-[1-(pyridine-4-carbonyl)-piperidin-4-yl]-ethylamino}-pyrimidin-4-yl)-oxazolidin-2-one(2 mg) in 8% yield.

HRMS(B) m/z 438.2379 (M+H)+; RT.: 1.82 min.

Example 480

To a solution ofS)-4-Isopropyl-3-[2-((S)-1-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-oxazolidin-2-one(16 mg, 0.48 mmol) in dichloromethane (1 mL) and DMF (1 mL) was addedHATU (20 mg, 0.05 mmol) and DiPEA (0.03 mL, 0.15 mmol) The reaction wasstirred at room temperature for 18 hours. The solvent is then removedunder vacuum. The crude material was then purified using reverse phaseC18 ODB column water-acetonitrile 0.1% TFA modifier to give(S)-4-Isopropyl-3-(2-{(S)-1-[1-(pyridine-4-carbonyl)-piperidin-4-yl]-ethylamino}-pyrimidin-3-yl)-oxazolidin-2-one(2 mg) in 8% yield.

HRMS(B) m/z 438.2379 (M+H)+; RT.: 1.83 min.

Example 481 & 482

To a solution of(S)-4-Isopropyl-3-[2-((S)-1-methyl-prop-2-ynylamino)-pyrimidin-4-yl]-oxazolidin-2-one(60 mg, 0.22 mmol) and benzyl azide (30 mg, 0.23 mmol) in water (0.5 mL)and DMSO (3 mL) was added copper sulfate pentahydrate (56 mg, 0.23 mmol)and L-ascorbic acid sodium salt (45 mg, 0.23 mmol). The reaction wasstirred for 48 hours at room temperature. The reaction mixture wasdiluted with EtOAc (75 mL) and washed with water (15 mL) and 1N solutionsodium bicarbonate (15 mL). The organic layer was dried over MgSO4,filtered and concentrated. The crude material was then purified onreverse phase using a C18 column water-acetonitrile TFA as a modifier,which also effected separation of the two diastereomer products(S)-3-{2-[(S)-1-(1-benzyl-1H-[1,2,3]triazol-4-yl)-ethylamino]-pyrimidin-4-yl}-4-isopropyl-oxazolidin-2-oneand(S)-3-{2-[(R)-1-(1-benzyl-1H-[1,2,3]triazol-4-yl)-ethylamino]-pyrimidin-4-yl}-4-isopropyl-oxazolidin-2-one

First Peak 481: HRMS(B) m/z 407.2070 (M+H)+; RT.: 2.26 min.

Second Peak 482: HRMS(B) m/z 407.2070 (M+H)+; RT.: 2.32 min.

Example 483 & 484

To a solution of(S)-4-Isopropyl-3-[2-((S)-1-methyl-prop-2-ynylamino)-pyrimidin-4-yl]-oxazolidin-2-one(82 mg, 0.30 mmol) and azidobenzene (36 mg, 0.30 mmol) in water (0.5 mL)and DMSO (3 mL) was added copper sulfate pentahydrate (75 mg, 0.23 mmol)and L-ascorbic acid sodium salt (60 mg, 0.23 mmol). The reaction wasstirred for 48 hours at room temperature. The reaction mixture wasdiluted with EtOAc (75 mL) and washed with water (15 mL) and 1N solutionsodium bicarbonate (15 mL). The organic layer was dried over MgSO4,filtered and concentrated. The crude material was then purified onreverse phase using a C18 column water-acetonitrile TFA as a modifier,which also effected separation of the two diastereomer products(S)-4-isopropyl-3-{2-[(S)-1-(1-phenyl-1H-[1,2,3]triazol-4-yl)-ethylamino]-pyrimidin-4-yl}-oxazolidin-2-oneand(S)-4-isopropyl-3-{2-[(R)-1-(1-phenyl-1H-[1,2,3]triazol-4-yl)-ethylamino]-pyrimidin-4-yl}-oxazolidin-2-one

First Peak 483: HRMS(B) m/z 393.1913 (M+H)+; RT.: 2.31 min.

Second Peak 484: HRMS(B) m/z 393.1913 (M+H)+; RT.: 2.40 min.

Example 485

To a room temperature solution of3-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloxazolidin-2-one (30 mg,0.122 mmol) in DMSO (300 μL) was treated with DIPEA (68 μL, 0.366 mmol)followed by addition of(S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethanamine (41.4 mg, 0.2mmol). The reaction was sealed, heated at 95° C. for ˜18 hr.Purification by reverse phase HPLC provided the trifluoroacetate salt of(S)-3-(5-fluoro-2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethylamino)pyrimidin-4-yl)-5,5-dimethyloxazolidin-2-one.(6.0 mg, white solid). ¹H NMR (400 MHz, METHANOL-d4) δ ppm 1.44-1.58 (m,12H) 3.50-3.74 (m, 1H) 3.88 (d, J=9.8 Hz 1H) 5.29 (d, J=7.04 Hz, 1H)7.38-7.45 (m, 2H) 7.6 (t, J=8.22 Hz 1H) 8.16 (d, J=3.13 Hz, 1H); HRMS(A)m/z 417.1360 (M+H)⁺, Rt 2.29 min.

The compounds in Table 11 were prepared using methods similar to thosedescribed for the preparation of Example 485.

TABLE 11

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

TABLE 12 Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 11. Example: Name ¹H NMR (400 MHz) ppm LCMS486: 3-(5-fluoro-2-((S)-1- (CD₃OD) 1.41-1.58 (m, 8 H) 3.55 (br. s., 1HRMS(A) (2-fluoro-4- H) 3.74-3.80 (m, 1 H) 4.17 (dd, J = 9.59, m/z(trifluoromethyl)phenyl)eth- 7.63 Hz, 1 H) 5.26-5.33 (m, 1 H) 7.39-403.1198 ylamino)pyrimidin-4-yl)-5- 7.45 (m, 2 H) 7.60 (t, J = 7.83 Hz,1 H) 8.15 (M + H)⁺, methyloxazolidin-2-one (d, J = 3.52 Hz, 1 H) Rt 2.20min 487: (S)-6-(5-fluoro-2-(1- (CD₃OD) 0.90 (m, 2 H) 1.18-1.27 (m, 2 H)HRMS(A) (2-fluoro-4- 1.53 (d, J = 7.04 Hz, 3 H) 4.21 (d, J = 9.39 m/z(trifluoromethyl)phenyl)eth- Hz, 1 H) 5.30 (d, J = 7.04 Hz, 1 H) 7.38-415.1204 ylamino)pyrimidin-4-yl)-4- 7.45 (m, 2 H) 7.60 (t, J = 7.83 Hz 1H) 8.17 (M + H)⁺, oxa-6- (d, J = 3.52 Hz, 1 H) Rt 2.31azaspiro[2.4]heptan-5-one min 488: (S)-3-(2-(1-(5-chloro- (CD₃OD) 8.22(d, J = 3.13 Hz, 1 H) 8.08 (d, HRMS(A) 6-(2,2,2- J = 1.96 Hz, 1 H) 7.84(d, J = 1.96 Hz, 1 H) m/z trifluoroethoxy)pyridin-3- 5.26-5.27 (m, 1 H)4.90 (q, 464.1125 yl)ethylamino)-5- J = 8.61 Hz, 3 H) 4.13-4.22 (m, 2 H)1.47- (M + H)⁺, fluoropyrimidin-4-yl)-4,4- 1.59 (m, 9H) Rt 2.28dimethyloxazolidin-2-one min 489: (S)-3-(2-(1-(5-chloro- (CD₃OD) 8.51(d, J = 1.57 Hz, 1 H) 8.23 (d, HRMS(A) 6-(1,1- J = 2.35 Hz, 1 H) 7.93(d, J = 1.56 Hz, 1 H) m/z difluoroethyl)pyridin-3- 4.99 (q, J = 6.52 Hz,1 H) 2.02 (t, 458.1573 yl)ethylamino)-5- J = 18.78 Hz, 3 H) 1.57 (d, J =7.43 Hz, 3 H) (M + H)⁺, fluoropyrimidin-4-yl)- 1.34-1.42 (m, 12 H) Rt2.02 4,4,5,5- min tetramethyloxazolidin-2- one 490:(S)-3-(2-(1-(5-chloro- (CD₃OD) 8.50 (d, J = 1.17 Hz, 1 H) 8.24 (d,HRMS(A) 6-(1,1- J = 2.35 Hz, 1 H) 7.93 (d, J = 1.57 Hz, 1 H) m/zdifluoroethyl)pyridin-3- 4.99 (q, J = 6.65 Hz, 1 H) 4.12- 430.1265yl)ethylamino)-5- 4.21 (m, 2 H) 2.01 (t, J = 18.78 Hz, 3 H) (M + H)⁺,fluoropyrimidin-4-yl)-4,4- 1.57 (d, J = 7.04 Hz, 3 H) 1.47 (s, 6 H) Rt2.05 dimethyloxazolidin-2-one min 491: (S)-3-(2-(1-(3-(4- (CD₃OD) 8.27(br. s., 1 H) 8.00 (d, J = 8.61 HRMS(A) chlorophenyl)-1,2,4- Hz, 3 H)7.52 (d, J = 8.61 Hz, 4 H) 5.29 (d, m/z oxadiazol-5- J = 7.04 Hz, 1 H)1.73 (s, 3 H) 1.44 (s, 3 H) 461.1512 yl)ethylamino)-5- 1.38 (s, 3 H)1.28 (s, 3 H) (M + H)⁺, fluoropyrimidin-4-yl)- Rt 2.37 4,4,5,5- mintetramethyloxazolidin-2- one 492: 3-(2-((S)-1-(3-(4- (CD₃OD) 8.27 (d, J= 1.57 Hz, 1 H) 8.00 (d, HRMS(A) chlorophenyl)-1,2,4- J = 8.61 Hz, 2 H)7.52 (d, J = 8.61 Hz, 2 H) m/z oxadiazol-5- 5.29 (m, 1 H) 4.44(m, 1 H)1.73 (d, J = 7.43 477.1349 yl)ethylamino)-5- Hz, 3 H) 1.44 (br. s., 3 H)1.26-1.35 (m, 6 (M + H)⁺, fluoropyrimidin-4-yl)-4,4,5- H) Rt 2.3 mintrimethyloxazolidin-2-one (1:1 mixture of diastereomers) 493:(S)-3-(2-(1-(3-(4- (CD₃OD) 8.28 (d, J = 2.35 Hz, 1 H) 8.00 (d, HRMS(A)chlorophenyl)-1,2,4- J = 8.61 Hz, 2 H) 7.51 (d, J = 8.61 Hz, 2 H) m/zoxadiazol-5- 5.29 (m, 1 H) 4.11-4.24 (m, 2 H) 1.73 (d, 433.1201yl)ethylamino)-5- J = 7.04 Hz, 3 H) 1.53 (s, 3 H) 1.30 (br. s., 3 (M +H)⁺, fluoropyrimidin-4-yl)-4,4- H) Rt 2.21 dimethyloxazolidin-2-one min494: (4S)-4-isopropyl-5- (CD₃OD) 8.11 (d, J = 6.26 Hz, 1 H) 7.71 (d,HRMS(A) methyl-3-(2-((S)-1- J = 7.43 Hz, 1 H) 7.29-7.40 (m, 4 H) 7.22-m/z phenylethylamino)pyrimidin- 7.28 (m, 1 H) 5.23 (br. s., 1 H)341.1985 4-yl)oxazolidin-2-one 4.82-4.91 (m, 1 H) 4.78 (br. s., 1 H)2.01 (M + H)⁺, (1:1 mixture of (br. s., 1 H) 1.59 (d, J = 7.04 Hz, 3 H)1.54 Rt 1.78 diastereomers) (d, J = 6.65 Hz, 3 H) 0.76 (br. s., 6 H) min495: (4S)-3-(5-fluoro-2- (CD₃OD) 7.87 (d, J = 3.13 Hz, 1 H) 6.95-HRMS(A) ((S)-1- 7.02 (m, 2 H) 6.91 (t, J = 7.63 Hz, 2 H) 6.75- m/zphenylethylamino)pyrimidin- 6.85 (m, 1 H) 4.52-4.61 (m, 2H) 4.00 (br.359.1891 4-yl)-4-isopropyl-5- s., 1 H) 1.49 (br. s., 1 H) 1.11 (dd, J =9.59, (M + H)⁺, methyloxazolidin-2-one 6.85 Hz, 6 H) 0.38 (d, J = 4.30Hz, 6 H) Rt 2.19 (1:1 mixture of min diastereomers) 496: (S)-4,4,5,5-(CD₃OD) 8.08 (d, J = 6.26 Hz, 1 H) 7.28- HRMS(A) tetramethyl-3-(2-(1-7.40 (m, 5 H) 7.18-7.25 (m, 1 H) 5.05 (q, m/zphenylethylamino)pyrimidin- J = 7.04 Hz, 1 H) 1.55-1.62 (m, 6H) 1.37341.1984 4-yl)oxazolidin-2-one (s, 3 H) 1.32 (s, 3H) (M + H)⁺, Rt 1.73min 497: (S)-3-(5-fluoro-2-(1- (CD₃OD) 8.18 (d, J = 2.74 Hz, 1 H) 7.30-HRMS(A) phenylethylamino)pyrimidin- 7.39 (m, 2 H) 7.23-7.30 (m, 2 H)7.12- m/z 4-yl)-4,4,5,5- 7.21 (m, 1 H) 4.90 (q, J = 6.91 Hz, 1 H) 1.50359.1891 tetramethyloxazolidin-2- (d, J = 7.04 Hz, 3 H) 1.42 (s, 3 H)1.36 (s, 3 (M + H)⁺, one H) 1.33 (s, 3H) Rt 2.16 min 498:4,4,5-trimethyl-3-(2- (CD₃OD) 8.09 (d, J = 6.65 Hz, 1 H) 7.53 (d,HRMS(A) ((S)-1- J = 7.04 Hz, 1 H) 7.45 (d, J = 7.04 Hz, 1 H) m/zphenylethylamino)pyrimidin- 7.30-7.40 (m, 8 H) 7.20-7.28(m, 2 H)327.1826 4-yl)oxazolidin-2-one 5.09 (t, J = 7.04 Hz, 2 H) 4.27-4.42 (m,2 (M + H)⁺, (1:1 mixture of H) 1.52-1.69 (m, 12 H) 1.32 (dd, J = 11.15,Rt 1.66 diastereomers) 6.46 Hz, 6 H) 0.82-1.20 (m, 6 H) min 499:3-(5-fluoro-2-((S)-1- (CD₃OD) 8.18 (d, J = 2.74 Hz, 1 H) 7.30- HRMS(A)phenylethylamino)pyrimidin- 7.37 (m, 2 H) 7.24-7.30 (m, 2 H) 7.11- m/z4-yl)-4,4,5- 7.21 (m, 1 H) 4.87-4.97 (m, 1 H) 4.31- 345.1735trimethyloxazolidin-2-one 4.46 (m, 1 H) 1.50 (d, J = 7.04 Hz, 3 H) 1.41(M + H)⁺, (1:1 mixture of (d, J = 10.96 Hz, 3 H) 1.29 (dd, J = 6.46,3.33 Rt 2.09 diastereomers) Hz, 3 H) 0.84-1.16 (br. s, 3 H) min 500:(S)-3-(5-fluoro-2-(1- (CD₃OD) 8.19 (d, J = 2.35 Hz, 1 H) 7.30- HRMS(A)phenylethylamino)pyrimidin- 7.37 (m, 2 H) 7.24-7.30 (m, 2 H) 7.13- m/z4-yl)-4,4- 7.21 (m, 1 H) 4.91 (q, J = 7.30 Hz, 1 H) 4.12 331.1573dimethyloxazolidin-2-one (q, J = 8.22 Hz, 2 H) 1.45-1.55 (m, 6 H) (M +H)⁺, 1.08 (br. s., 3 H) Rt 1.98 min 501: (4S)-3-(2-((S)-1-(5- ¹H NMR(400 MHz, CD₃OD) δ ppm 8.14 HRMS(A) chloro-6-(2,2,2- (d, J = 6.65 Hz, 1H) 8.10 (d, J = 1.96 Hz, 1 m/z trifluoroethoxy)pyridin-3- H) 7.86 (d, J= 2.35 Hz, 1 H) 7.57 (d, J = 6.26 474.1523 yl)ethylamino)pyrimidin-4-Hz, 1 H) 5.17 (d, J = 6.65 Hz, 1 H) 4.92 (q, (M + H)⁺,yl)-4-isopropyl-5- J = 8.87 Hz, 1 H) 4.80-4.84 (m, 1H) 2.04 Rt 2.18methyloxazolidin-2-one (br. s., 2 H) 1.55 (dd, J = 15.85, 6.85 Hz, 6 min(1:1 mixture of H) 0.79 (br. s., 6 H) diastereomers) 502:(S)-3-(2-(1-(5-chloro- (CD₃OD) 8.07-8.16 (m, 1 H) 7.89 (d, HRMS(A)6-(2,2,2- J = 1.96 Hz, 1 H) 7.32 (d, J = 6.26 Hz, 1 H) m/ztrifluoroethoxy)pyridin-3- 5.08 (q, J = 6.78 Hz, 1 H) 1.55-1.65 (m, 8474.1534 yl)ethylamino)pyrimidin-4- H) 1.37 (d, J = 11.35 Hz, 6 H) 1.20(d, (M + H)⁺, yl)-4,4,5,5- J = 11.35 Hz, 3 H) Rt 2.16tetramethyloxazolidin-2- min one 503: 3-(2-((S)-1-(5-chloro- (CD₃OD)8.47 (d, J = 5.87 Hz, 1 H) 8.11 (d, HRMS(A) 6-(2,2,2- J = 2.35 Hz, 3H)7.99 (d, J = 6.26 Hz, 1 H) m/z trifluoroethoxy)pyridin-3- 7.88 (d, J =1.96 Hz, 3 H) 7.39 (d, J = 6.26 Hz, 460.1375 yl)ethylamino)pyrimidin-4-2 H) 7.32 (d, J = 6.65 Hz, 2 H) 5.04-5.13 (M + H)⁺, yl)-4,4,5- (m, 1 H)4.87-4.98 (m, 2 H) 4.45 (d, Rt 2.08, trimethyloxazolidin-2-one J = 6.65Hz, 1 H) 4.35 (dd, J = 13.69, 6.65 2.11 min (1:2 mixture of Hz, 2 H)1.67(d, J = 4.70 Hz, 9 H) 1.59 (d, diastereomers) J = 7.04 Hz, 12 H)1.39 (d, J = 6.65 Hz, 3 H) 1.33 (t, J = 6.06 Hz, 6 H) 0.99-1.27 (m, 9 H)504: (S)-3-(2-(1-(5-chloro- (CD₃OD) 8.09-8.17 (m, 1 H) 7.88 (d, HRMS(A)6-(2,2,2- J = 2.35 Hz, 1 H) 7.38 (d, J = 6.26 Hz, 1 H) m/ztrifluoroethoxy)pyridin-3- 4.91 (q, J = 8.61 Hz, 1 H) 4.06-4.16(m, 2446.1219 yl)ethylamino)pyrimidin-4- H) 1.71 (m, 5 H) 1.58 (d, J = 7.04Hz, 3 H) (M + H)⁺, yl)-4,4-dimethyloxazolidin- 1.28 (br. s., 3 H) Rt2.01 2-one min 505: (S)-3-(2-(1-(2,5- (CD₃OD) 8.15 (d, J = 3.13 Hz, 1 H)6.92- HRMS(A) difluoro-4- 7.08 (m, 2 H) 5.21 (q, J = 6.78 Hz, 1 H) 4.44-m/z isopropylphenyl)ethylami- 4.58 (m, 2 H) 4.10-4.22 (m, 1H) 3.96 (m,381.1544 no)-5-fluoropyrimidin-4- 1 H) 3.07-3.23 (m, 1 H) 1.48 (d, J =7.04 (M + H)⁺, yl)oxazolidin-2-one Hz, 5 H) 1.21 (m, 6 H) Rt 2.26 min506: (S)-3-(2-(1-(4-bromo- (CD₃OD) 8.15 (d, J = 3.52 Hz, 1 H) 7.39 (dd,HRMS(A) 2,5- J = 9.00, 5.48 Hz, 1 H) 7.24 (dd, J = 9.19, m/zdifluorophenyl)ethylami- 6.46 Hz, 1 H) 5.19 (q, J = 7.04 Hz,1 H) 4.44-417.018 no)-5-fluoropyrimidin-4- 4.58 (m, 2 H) 4.09-4.23 (m, 1 H) 3.94(M + H)⁺, t yl)oxazolidin-2-one (br. s., 1 H) 1.48 (d, J = 7.04 Hz, 3 H)2.07 min 507: (S)-3-(2-(1-(3-(4- (CD₃OD) 8.09 (d, J = 6.26 Hz, 1 H) 7.91(d, HRMS(A) chlorophenyl)-1,2,4- J = 8.61 Hz, 2 H) 7.43 (d, J = 8.61 Hz,3 H) m/z oxadiazol-5- 5.35 (q, J = 7.30 Hz, 1 H) 3.97-4.09 (m, 2415.1287 yl)ethylamino)pyrimidin-4- H) 1.69 (d, J = 7.43 Hz, 3 H) 1.62(s, 3 H) (M + H)⁺, yl)-4,4-dimethyloxazolidin- 1.14-1.45 (m, 3 H) Rt2.14 2-one min

Example 508

A solution of3-(2,6-dichloropyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one (70.0 mg,0.267 mmol), (S)-(−)-1-phenylethanamine (0.034 mL, 0.267 mmol, 1.0equiv), and N-ethyl-N-isopropylpropan-2-amine (0.070 mL, 0.401 mmol, 1.5equiv) in DMSO (1.5 mL) was heated at 85° C. for 2-4 h. Purification byreverse phase HPLC provided the trifluoroacetate salt of(S)-3-(6-chloro-2-(1-phenylethylamino)pyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one(20.0 mg, white solid) in 16% yield. ¹H NMR (300 MHz, CDCl₃) δ 7.36 (s,1H), 7.33-7.31 (m, 4H), 7.26-7.21 (m, 1H), 5.48 (br m, 1H), 4.02-3.94(m, 2H), 1.65 (s, 3H), 1.55 (d, J=6.9 Hz, 3H), 1.26 (s, 3H); HRMS(A) m/z347.1274 (M+H)⁺, Rt 2.32 min.

The compounds in Table 13 were prepared using methods similar to thosedescribed for the preparation of Example 508.

TABLE 13

509

510

511

512

513

TABLE 14 Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 13. Example: Name ¹H NMR (400 MHz) δ ppm LCMS509: (S)-3-(6-chloro-2-(1- (CDCl₃) 7.36 (s, 1H), 7.33-7.31 (m, HRMS(A)phenylethylamino)pyrimidin- 4H), 7.26-7.21 (m, 1H), 5.48 (br m, 1H), m/z4-yl)-4,4- 4.02-3.94 (m, 2H), 1.65 (s, 3H), 1.55 (d, 347.1274dimethyloxazolidin-2-one J = 6.9 Hz, 3H), 1.26(s, 3H) (M + H)⁺, Rt 2.32min 510: (S)-3-(6-chloro-2-(1- (CDCl₃) 8.00 (d, J = 8.4 Hz, 2 H), 7.53(s, HRMS(A) (3-(4-chlorophenyl)-1,2,4- 1H), 7.47 (d, J = 8.4 Hz, 2H),5.44-5.29 m/z oxadiazol-5- (br m, 1H), 4.09-4.02 (m, 2H), 1.78 (d,449.0905 yl)ethylamino)pyrimidin-4- J = 7.1 Hz, 3H), 1.72 (s, 3H), 1.40(br s, 3H) (M + H)⁺, yl)-4,4-dimethyloxazolidin- Rt 2.51 2-one min 511:(S)-3-(6-chloro-2-(1- (CDCl₃) 8.00 (d, J = 8.7 Hz, 2H), 7.62 (s, HRMS(A)(3-(4-chlorophenyl)-1,2,4- 1H), 7.47 (d, J = 8.7 Hz, 2H), 5.32 (br m,m/z oxadiazol-5- 1H), 4.49-4.43 (m, 2H), 4.17-4.14 (m, 421.0585yl)ethylamino)pyrimidin-4- 1H), 3.95-3.60 (br m, 1H), 1.77 (d, J = (M +H)⁺, yl)oxazolidin-2-one 7.1 Hz, 3H) Rt 2.32 min 512:(S)-3-(6-chloro-2-(1- (CDCl₃) 7.76 (s, 1H), 7.60 (s, 1H), 7.50 (s, LCMSm/z (2-fluoro-4-(1-methyl-1H- 1H), 7.34-7.28 (m, 1H), 7.20 (dd, J = 7.8,417.2 pyrazol-4- 1.6 Hz, 1H), 7.15-7.09 (m, 1H), 5.30 (br (M + H)+yl)phenyl)ethylamino)pyrim- m, 1H), 4.49-4.42 (m, 2H), 4.28-4.23idin-4-yl)oxazolidin-2- (m, 1H), 3.97 (s, 3H), 3.92 (br m, 1H), 1.56 one(d, J = 6.7 Hz, 3H) 513: (S)-3-(2-(1-(3-(4- (CDCl₃) 7.99 (d, J = 8.4 Hz,2H), 7.45 (d, HRMS(A) chlorophenyl)-1,2,4- J = 8.4 Hz, 2H), 7.11 (s,1H), 5.38 (br m, m/z oxadiazol-5- 1H), 4.08-4.03 (m, 2H), 1.78 (d, J =7.0 433.1201 yl)ethylamino)-6- Hz, 3H), 1.73 (s, 3H), 1.38 (brs, 3H)(M + H)⁺, fluoropyrimidin-4-yl)-4,4- Rt 2.42 dimethyloxazolidin-2-onemin

Example 514

A solution of(S)-3-(2-(1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-6-fluoropyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one(29.0 mg, 0.053 mmol) and 1 N aqueous hydrochloric acid (0.70 mL) in1,4-dioxane (0.7 mL) was heated at 100° C. for 4 h. After cooling toroom temperature, the reaction mixture was diluted with dichloromethane(10 mL), washed with saturated aqueous sodium bicarbonate solution (10mL), dried over Na₂SO₄, filtered and concentrated. Purification byreverse phase HPLC provided the trifluoroacetate salt of(S)-3-(2-(1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-6-hydroxypyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one(16 mg, white solid) in 55% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d,J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 6.71 (br s, 1H), 5.33 (br m, 1H),4.02-3.99 (m, 2H), 1.83 (d, J=7.1 Hz, 3H), 1.68 (s, 3H), 1.31 (s, 3H);HRMS(A) m/z 431.1245 (M+H)⁺, Rt 1.80 min.

Example 515

Step 1

To round bottom flask containing(R)—N—((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(87 mg, 0.29 mmol) was added dioxane (2 mL). To this solution was addedhydrochloric acid in dioxane (4.0M, 0.15 ml, 0.59 mmol) and the solutionallowed to stir 10 min at room temperature.

Volatiles were removed. Et₂O (10 mL) was added and the reaction mixturesonnicated. The volatiles were removed again. Et₂O (10 ml) was againadded and the suspension sonnicated. Solid material was collected andwashed with Et₂O to afford an HCl salt of(S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethanamine (42 mg, 0.18mmol, 63% yield) as a white solid. LCMS m/z 194.1 (M+H)⁺, Rt 0.60 min.

Step 2

To a microwave vial with stir bar was added(S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (30 mg, 0.12mmol) and DMSO (1 mL). To this reaction mixture was added(S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethanamine (51 mg, 0.22mmol) and DIEA (0.09 ml, 0.50 mmol). The vial was capped and thereaction mixture was heated in a preheated oil bath at 110° C. for 18hr. Solution was purified by reverse phase HPLC. Product fractionscombined, frozen and lyophilized to afford(S)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one(3.3 mg, 6.3 μmol, 5% yield) as a TFA salt. ¹H NMR (400 MHz, CD₃OD) δ0.58 (br. s., 3H) 0.77 (td, J=5.23, 1.76 Hz, 5H) 0.80-0.86 (m, 2H) 1.38(s, 3H) 1.57 (d, J=6.94 Hz, 3H) 4.34-4.41 (m, 2H) 4.67 (br. s., 1H) 5.33(d, J=7.97 Hz, 1H) 6.95-7.05 (m, 2H) 7.22 (t, J=7.97 Hz, 1H) 7.67 (d,J=6.85 Hz, 1H) 8.14 (d, J=6.65 Hz, 1H). LCMS m/z 399.4 (M+H)⁺, Rt 0.93min. HRMS(A) m/z 399.2202 (M+H)⁺, Rt 2.23 min.

The compounds in Table 15 were prepared using methods similar to thosedescribed for the preparation of Examples 515.

TABLE 15

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

545

546

TABLE 16 Table 16. Chemical name, NMR chemical shifts and LCMS signalfor each compound listed in Table 15. Example: Name ¹H NMR (400 MHz) δppm LCMS 516: (S)-3-(2-((S)-1-(6- (DMSO) 0.46 (br. s., 3 H) 0.63 (br.s., 3 H) HRMS(A) tert-butylpyridin-3-yl) 1.35 (s, 9 H) 1.50 (d, J = 6.99Hz, 3 H) 4.34 m/z ethylamino)pyrimidin-4-yl)- (d, J = 7.92 Hz, 2 H) 4.59(br. s., 1 H) 5.14 384.2410 4-isopropyloxazolidin-2- (br. s., 1 H) 7.32(d, J = 5.92 Hz, 1 H) 7.70 (M + H)⁺, one (br. s., 1 H) 8.03 (br. s., 1H) 8.24 (br. s., 2 Rt 1.34 H) 8.59 (br. s., 1 H) 517:(S)-3-(2-((S)-1-(6- (DMSO) 0.55 (br. s., 6 H) 1.25-1.38 (s, 9 HRMS(A)tert-butylpyridin-3- H) 1.47 (d, J = 7.04 Hz, 3 H) 4.26 (br. s., 1 m/zyl)ethylamino)-5- H) 4.45-4.59 (m, 2 H) 4.98 (br. s., 1 H) 402.2314fluoropyrimidin-4-yl)-4- 7.66 (br. s., 1 H) 8.11 (br. s., 2 H) 8.41 (br.(M + H)⁺, isopropyloxazolidin-2-one s., 1 H) 8.60 (br. s., 1 H) Rt 1.45518: (S)-4-isopropyl-3-(2- HRMS(A) ((S)-1-(4-(1-methyl- m/z cyclopropyl)381.2295 phenyl)ethylamino)pyrim- (M + H)⁺, idin-4-yl)oxazolidin-2-oneRt 2.10 519: (S)-3-(2-((S)-1-(4- (DMSO) 0.49 (br. s., 3 H) 0.68 (br. s.,3 H) HRMS(A) (1,5-dimethyl-1H-pyrazol- 1.48 (d, J = 7.04 Hz, 6 H) 2.33(s, 3 H) 3.76 m/z 4- (s, 3 H) 4.63 (br. s., 1 H) 4.75-4.82 (m, 1421.2362 yl)phenyl)ethylamino)pyrim- H) 5.03 (br. s., 2 H) 7.30-7.37 (m,4 H) (M + H)⁺, idin-4-yl)-4- 7.50 (s, 1 H) 8.22 (br. s., 1 H) 8.36 (br.s., Rt 1.58 isopropyloxazolidin-2-one 1H) 520: (S)-3-(2-((S)-1-(2-(DMSO) 0.40 (br. s., 3 H) 0.57 (br. s., 3 H) HRMS(A)fluoro-4-(trifluoromethyl) 1.40 (br. s., 1 H) 1.47 (d, J = 7.04 Hz, 3 H)m/z phenyl)ethylamino)pyrim- 4.24-4.37 (m, 2 H) 4.49 (br. s., 1 H) 5.23413.1602 idin-4-yl)-4- (br. s., 1 H) 7.30 (d, J = 5.82 Hz, 1 H) 7.48-(M + H)⁺, isopropyloxazolidin-2-one 7.59 (m, 2 H) 7.65 (d, J = 10.56 Hz,1 H) Rt 2.16 8.21 (d, J = 18.58 Hz, 2 H) 521: (S)-3-(2-((S)-1-(4-(CD₃OD) 0.61 (br. s., 3 H) 0.64-0.69 (m, 3 HRMS(A) cyclopropyl-2- H)0.77 (br. s., 3 H) 0.96-1.04 (m, 2 H) m/z fluorophenyl)ethylami- 1.57(d, J = 6.99 Hz, 3 H) 1.88-1.95 (m, 1 385.2042 no)pyrimidin-4-yl)-4- H)4.39 (d, J = 5.97 Hz, 2 H) 4.69 (br. s., 1 (M + H)⁺,isopropyloxazolidin-2-one H) 5.33 (br. s., 1 H) 6.82 (dd, J = 12.08, Rt2.06 1.71 Hz, 1 H) 6.88 (d, J = 7.97 Hz, 1 H) 7.19 (t, J = 8.31 Hz, 1 H)7.70 (d, J = 6.90 Hz, 1 H) 8.14 (d, J = 7.04 Hz, 1 H) 522:(S)-3-(2-((S)-1-(6- (CD₃OD) 0.65-0.83 (m, 6 H) 1.14-1.20 HRMS(A)cyclopropylpyridin-3- (m, 2 H) 1.37-1.43 (m, 2 H) 1.64 (d, m/zyl)ethylamino)pyrimidin-4- J = 7.09 Hz, 3 H) 2.26-2.37 (m, 1 H) 4.36-368.2097 yl)-4-isopropyloxazolidin- 4.39 (m, 2 H) 4.68 (br. s., 1 H)5.25 (q, (M + H)⁺, 2-one J = 6.75 Hz, 1 H) 7.57 (d, J = 8.51 Hz, 1 H) Rt1.12 7.63 (br. s., 1 H) 8.18 (d, J = 5.92 Hz, 1 H) 8.33 (d, J = 7.24 Hz,1 H) 8.57 (d, J = 2.10 Hz, 1 H) 523: (S)-4-isopropyl-3-(2- (CD₃OD)0.59-0.84 (m, 6 H) 1.08-1.15 HRMS(A) ((S)-1-(6-(1- (m, 2 H) 1.22-1.28(m, 2 H) 1.56 (s, 3 H) m/z methylcyclopropyl)pyridin- 1.64 (d, J = 7.09Hz, 3 H) 4.35-4.39 (m, 2 382.2247 3-yl)ethylamino)pyrimidin- H) 4.69(br. s., 1 H) 5.21-5.32 (m, 1 H) (M + H)⁺, 4-yl)oxazolidin-2-one 7.62(br. s., 1 H) 7.79 (d, J = 8.46 Hz, 1 H) Rt 1.30 8.18 (d, J = 6.11 Hz, 1H) 8.33 (d, J = 7.14 Hz, 1 H) 8.57 (d, J = 2.20 Hz, 1 H) 524:(S)-3-(2-((S)-1-(4-(1- (CD₃OD) 0.60 (br. s., 3 H) 0.78 (br. s., 3 H)HRMS(A) ethoxycyclopropyl)-2- 0.92-0.98 (m, 2 H) 1.15 (t, J = 7.07 Hz, 3m/z fluorophenyl)ethylami- H) 1.19-1.26 (m, 2 H) 1.59 (d, J = 6.99 Hz,429.2310 no)pyrimidin-4-yl)-4- 3 H) 1.78 (br. s., 1 H) 3.43 (q, J = 7.09Hz, 2 (M + H)⁺, isopropyloxazolidin-2-one H) 4.40 (d, J = 5.72 Hz, 2 H)4.70 (d, J = 3.91 Rt 2.08 Hz, 1 H) 5.38 (br. s., 1 H) 7.06 (s, 1 H)7.07-7.12 (m, 1 H) 7.31 (t, J = 7.95 Hz, 1 H) 7.73 (d, J = 7.04 Hz, 1 H)8.15 (d, J = 6.90 Hz, 1 H) 525: (S)-4-isopropyl-3-(2- (DMSO) 0.47 (br.s., 3 H) 0.69 (br. s., 3 H) HRMS(B) ((S)-1-(4-(1-methyl-1H- 1.45 (d, J =6.99 Hz, 3 H) 1.81 (br. s., 1 H) m/z pyrazol-4- 3.84 (s, 3 H) 4.33 (d, J= 13.45 Hz, 2 H) 407.2179 yl)phenyl)ethylamino)pyrim- 4.62 (br. s., 1 H)4.99 (br. s., 1 H) 7.24- (M + H)⁺, idin-4-yl)oxazolidin-2- 7.33 (m, 3 H)7.46 (d, J = 8.27 Hz, 2 H) 7.79 Rt one (d, J = 0.73 Hz, 1 H) 8.06 (s, 1H) 8.18 (br. 2.44 min s., 1 H) 526: (S)-3-(2-((S)-1-(2- (CD₃OD) 0.59(br. s., 3 H) 0.78 (br. s., 3 H) HRMS(A) fluoro-4- 1.23 (dd, J = 6.90,1.03 Hz, 6 H) 1.58 (d, m/z isopropylphenyl)ethylami- J = 6.99 Hz, 3 H)2.91 (dt, J = 13.78, 6.93 Hz, 387.2207 no)pyrimidin-4-yl)-4- 1 H) 4.39(d, J = 5.97 Hz, 2 H) 4.69 (br. s., 1 (M + H)⁺,isopropyloxazolidin-2-one H) 5.35 (br. s., 1 H) 6.97-7.06 (m, 2 H) Rt2.20 7.20-7.28 (m, 1 H) 7.73 (d, J = 6.99 Hz, 1 H) 8.15 (d, J = 6.90 Hz,1 H) 527: 1-(3-fluoro-4-((S)-1- (CD₃OD) 0.61 (br. s., 3 H) 0.75 (br. s.,3 H) HRMS(A) (4-((S)-4-isopropyl-2- 1.40-1.50 (m, 2 H) 1.57 (d, J = 6.94Hz, 3 m/z oxooxazolidin-3- H) 1.71-1.79 (m, 2 H) 4.37 (d, J = 6.50 Hz,410.1999 yl)pyrimidin-2-ylamino) 2 H) 4.66 (br. s., 1 H) 5.34 (d, J =6.55 Hz, 1 (M + H)⁺, ethyl)phenyl)cyclopropane H) 7.07-7.18 (m, 2 H)7.36 (t, J = 8.19 Hz, Rt 1.82 carbonitrile 1 H) 7.64 (d, J = 6.65 Hz, 1H) 8.15 (d, J = 6.60 Hz, 1 H) 528: (S)-3-(2-((S)-1-(2- (CD₃OD) 0.58 (br.s., 3 H) 0.78 (br. s., 3 H) HRMS(A) fluoro-4-(1-methyl-1H- 1.62 (d, J =7.04 Hz, 3 H) 1.82 (br. s., 1 H) m/z pyrazol-4- 3.92 (s, 3 H) 4.40 (d, J= 6.26 Hz, 2 H) 4.70 425.2112 yl)phenyl)ethylamino)pyrim- (br. s., 1 H)5.39 (br. s., 1 H) 7.29-7.39 (M + H)⁺, idin-4-yl)-4- (m, 3 H) 7.78 (d, J= 7.04 Hz, 1 H) 7.82 (s, 1 Rt 1.64 isopropyloxazolidin-2-one H) 7.99 (s,1 H) 8.16 (d, J = 7.04 Hz, 1 H) 529: (S)-3-(2-((S)-1-(2- (CD₃OD) 0.59(br. s., 3 H) 0.79 (br. s., 3 H) HRMS(A) fluoro-4-(1H-pyrazol-4- 1.63(d, J = 6.94 Hz, 3 H) 1.84 (br. s., 1 H) m/z yl)phenyl)ethylamino)pyrim-4.40 (d, J = 6.26 Hz, 2 H) 4.71 (br. s., 1 H) 411.1949 idin-4-yl)-4-5.40 (br. s., 1 H) 7.29-7.36 (m, 1 H) 7.37- (M + H)⁺,isopropyloxazolidin-2-one 7.43 (m, 2 H) 7.78 (d, J = 7.09 Hz, 1 H) 7.99Rt 1.52 (s, 2 H) 8.17 (dd, J = 6.36, 1.86 Hz, 1 H) 530: 2-chloro-N-(DMSO) 0.55 (br. s., 3 H) 0.78 (br. s., 3 H) HRMS(A)cyclopentyl-4-((S)-1-(4- 1.42 (d, J = 7.09 Hz, 3 H) 1.50 (d, J = 4.65m/z ((S)-4-isopropyl-2- Hz, 4 H) 1.64 (br. s., 2 H) 1.83 (d, J = 6.46472.2117 oxooxazolidin-3- Hz, 3 H) 4.14 (dd, J = 12.72, 6.60 Hz, 1 H)(M + H)⁺, yl)pyrimidin-2- 4.34 (br. s., 2 H) 4.64 (br. s., 1 H) 5.03(br. Rt 1.82 ylamino)ethyl)benzamide s., 1 H) 7.25 (d, J = 5.77 Hz, 1 H)7.31 (s, 2 H) 7.42 (s, 1 H) 8.19 (br. s., 1 H) 8.27 (br. s., 1 H) 531:2-chloro-N- (DMSO) 0.55 (br. s., 3 H) 0.78 (br. s., 4 H) HRMS(A)cyclohexyl-4-((S)-1-(4- 1.18-1.34 (m, 4 H) 1.42 (d, J = 7.04 Hz, 3 m/z((S)-4-isopropyl-2- H) 1.56 (d, J = 12.08 Hz, 1 H) 1.69 (d, 486.2275oxooxazolidin-3- J = 12.86 Hz, 3 H) 1.81 (br. s., 3 H) 4.34 (br. (M +H)⁺, yl)pyrimidin-2- s., 2 H) 4.63 (br. s., 1 H) 5.03 (br. s., 1 H) Rt1.94 ylamino)ethyl)benzamide 7.26 (d, J = 5.82 Hz, 1 H) 7.31 (s, 2 H)7.43 (s, 1 H) 8.03 (br. s., 1 H) 8.18 (br. s., 2 H) 532:2-chloro-N-((1r,4S)- (DMSO) 0.54 (br. s., 3 H) 0.77 (br. s., 3 H)HRMS(A) 4-hydroxycyclohexyl)-4- 1.18-1.30 (m, 5 H) 1.36 (s, 1 H) 1.42(d, m/z ((S)-1-(4-((S)-4-isopropyl- J = 7.04 Hz, 3 H) 1.81 (d, J = 9.19Hz, 5 H) 502.2226 2-oxooxazolidin-3- 3.36 (br. s., 1 H) 4.33 (br. s., 2H) 4.63 (br. (M + H)⁺, yl)pyrimidin-2- s., 1 H) 5.02 (br. s., 1 H) 7.25(d, J = 5.77 Rt 1.40 ylamino)ethyl)benzamide Hz, 1 H) 7.30 (s, 2 H) 7.42(s, 1 H) 8.17 (br. s., 2 H) 533: (S)-3-(2-((S)-1-(3- (DMSO) 0.40-0.73(m, 6 H) 1.40 (d, HRMS(A) (cyclopentyloxy)phenyl)eth- J = 6.99 Hz, 3 H)1.47-1.70 (m, 6 H) 1.83 m/z ylamino)pyrimidin-4-yl)- (dd, J = 16.80,6.72 Hz, 3 H) 4.31 (d, J = 8.75 411.2402 4-isopropyloxazolidin-2- Hz, 2H) 4.58 (br. s., 1 H) 4.71 (br. s., 1 H) (M + H)⁺, one 4.94 (br. s., 1H) 6.69 (dd, J = 7.95, 2.03 Hz, Rt 2.15 1 H) 6.81 (d, J = 8.31 Hz, 2 H)7.09-7.19 min (m, 1 H) 7.27 (d, J = 6.06 Hz, 1 H) 8.16 (br. s., 2 H)534: (S)-3-(2-((S)-1-(3- (DMSO) 0.47 (br. s., 3 H) 0.65 (br. s., 3 H)HRMS(A) (cyclohexyloxy)phenyl)eth- 1.14-1.36 (m, 5 H) 1.40 (d, J = 7.04Hz, 3 m/z ylamino)pyrimidin-4-yl)-4- H) 1.44-1.54 (m, 1 H) 1.65 (d, J =9.34 Hz, 425.2565 isopropyloxazolidin-2-one 2 H) 1.72-1.91 (m, 3 H)4.11-4.39 (m, 3 (M + H)⁺, H) 4.57 (br. s., 1 H) 4.94 (br. s., 1 H) 6.71Rt 2.26 (dd, J = 7.85, 1.88 Hz, 1 H) 6.80 (br. s., 2 H) min 7.14 (t, J =8.07 Hz, 1 H) 7.26 (d, J = 6.02 Hz, 1 H) 8.16 (br. s., 2 H) 535:(S)-3-(2-((S)-1-(3- (DMSO) 0.50 (br. s., 3 H) 0.68 (br. s., 3 H) HRMS(A)(cycloheptyloxy)phenyl)eth- 1.43 (d, J = 7.04 Hz, 5 H) 1.53 (d, J = 2.98m/z ylamino)pyrimidin-4-yl)- Hz, 4 H) 1.58-1.71 (m, 4 H) 1.73-1.97439.2712 4-isopropyloxazolidin-2- (m, 3 H) 4.34 (d, J = 8.46 Hz, 2 H)4.38- (M + H)⁺, one 4.46 (m, 1 H) 4.60 (br. s., 1 H) 4.98 (br. s., Rt2.41 1 H) 6.70 (dd, J = 8.14, 2.03 Hz, 1 H) 6.76- min 6.89 (m, 2 H) 7.18(t, J = 7.87 Hz, 1 H) 7.30 (d, J = 6.02 Hz, 1 H) 8.20 (br. s., 2 H) 536:(S)-3-(2-((S)-1-(3- (DMSO) 0.49 (br. s., 3 H) 0.67 (br. s., 3 H) HRMS(A)isopropoxyphenyl)ethylami- 1.09-1.28 (m, 7 H) 1.32-1.50 (m, 3 H) m/zno)pyrimidin-4-yl)-4- 4.23-4.39 (m, 2 H) 4.52 (dt, J = 12.04, 6.08385.2248 isopropyloxazolidin-2-one Hz, 1 H) 4.60 (br. s., 1 H) 4.96 (br.s., 1 H) (M + H)⁺, 6.71 (dd, J = 8.00, 1.98 Hz, 1 H) 6.82 (br. s., Rt1.92 2H) 7.15 (t, J = 8.09 Hz, 1 H) 7.30 (d, min J = 6.02 Hz, 1 H) 8.18(br. s., 1 H) 8.28 (br. s., 1 H) 537: (S)-3-(5-fluoro-2-((S)- (DMSO)0.49 (br. s., 6 H) 0.92 (d, J = 6.7 HRMS(A) 1-(3- Hz, 6 H) 1.37 (d, J =7.04 Hz, 3 H) 1.93 m/z isobutoxyphenyl)ethylami- (dquin, J = 13.25,6.60, 6.60, 6.60, 6.60 Hz, 417.231 no)pyrimidin-4-yl)-4- 1 H) 3.59-3.70(m, 2 H) 3.94-4.31 (m, 3 (M + H)⁺, isopropyloxazolidin-2-one H) 4.45(br. s., 1 H) 6.69 (dd, J = 8.17, 1.76 Rt 2.53 Hz, 1 H) 6.80-6.89 (m, 2H) 7.13 (t, min J = 7.83 Hz, 1H) 7.92 (br. s., 1 H) 8.34 (br. s., 1 H)538: (S)-3-(5-fluoro-2-((S)- (DMSO) 1.41 (d, J = 7.04 Hz, 6 H) 1.83-HRMS(A) 1-(3-((S)-tetrahydrofuran- 1.93 (m, 1 H) 2.11-2.23 (m, 1 H)3.68- m/z 3- 4.04 (m, 8 H) 4.25 (br. s., 1 H) 4.49 (br. s., 431.2098yloxy)phenyl)ethylami- 2 H) 4.80 (br. s., 1 H) 4.95 (dd, J = 6.06, (M +H)⁺, no)pyrimidin-4-yl)-4- 4.65 Hz, 1 H) 6.72 (dd, J = 8.02, 2.10 Hz, 1Rt 2.01 isopropyloxazolidin-2-one H) 6.83-6.94 (m, 2 H) 7.19 (t, J =7.87 Hz, min 1 H) 7.96 (br. s., 1 H) 8.38 (br. s., 1 H) 539:(4S)-4-isopropyl-3-(2- (DMSO) 0.47 (br. s., 3 H) 0.66 (br. s., 3 H)HRMS(A) ((1S)-1-(3-(tetrahydro-2H- 1.39 (d, J = 6.99 Hz, 3 H) 1.44-2.00(m, 5 m/z pyran-3- H) 3.32-3.50 (m, 2 H) 3.54-3.88 (m, 3 H) 427.2353yloxy)phenyl)ethylami- 4.23-4.37 (m, 2 H) 4.61 (br. s., 1H) 4.90 (M +H)⁺, no)pyrimidin-4-yl)oxazolidin-2- (br. s., 1H) 6.74 (d, J = 8.36 Hz,1 H) 6.85 Rt 1.75 one (d, J = 13.55 Hz, 2 H) 7.15 (t, J = 7.87 Hz, 1 minH) 7.25 (d, J = 5.97 Hz, 1 H) 8.06 (br. s., 1 H) 8.16 (br. s., 1 H) 540:(S)-4-isopropyl-3-(2- (DMSO) 0.50 (br. s., 3 H) 0.66 (br. s., 3 H)HRMS(A) ((S)-1-(3- 1.42 (d, J = 7.04 Hz, 3 H) 1.75 (br. s., 1 H) m/zphenoxyphenyl)ethylami- 4.27-4.37 (m, 2 H) 4.55-4.62 (m, 1 H) 419.2092no)pyrimidin-4- 4.97-5.07 (m, 1 H) 6.78 (dd, J = 8.02, 1.81 (M + H)⁺,yl)oxazolidin-2-one Hz, 1 H) 6.87 (d, J = 7.53 Hz, 2 H) 6.96 (br. Rt2.12 s., 1 H) 7.04-7.14 (m, 2 H) 7.25-7.37 (m, min 4 H) 8.17 (d, J =4.99 Hz, 1 H) 8.36 (br. s., 1 H) 541: (S)-3-(5-fluoro-2-((S)- (DMSO)0.44-0.65 (m, 6 H) 1.37 (d, HRMS(A) 1-(3- J = 6.99 Hz, 3 H) 4.08-4.40(m, 2 H) 4.45 m/z phenoxyphenyl)ethylami- (br. s., 1 H) 4.82 (br. s., 1H) 6.75 (dd, 437.1992 no)pyrimidin-4-yl)-4- J = 8.07, 1.37 Hz, 1 H) 6.86(d, J = 7.48 Hz, 2 (M + H)⁺, isopropyloxazolidin-2-one H) 6.95 (br. s.,1 H) 7.03-7.11 (m, 2 H) Rt 2.45 7.28 (dt, J = 19.78, 7.86 Hz, 3 H) 7.94(br. min s., 1 H) 8.33 (br. s., 1 H) 542: (S)-3-(5-fluoro-2-((S)- (DMSO)0.56 (br. s., 6 H) 1.18 (d, J = 2.35 HRMS(A) 1-(4- Hz, 3 H) 1.20 (d, J =2.30 Hz, 3 H) 1.36 (d, m/z isopropoxyphenyl)ethylami- J = 7.04 Hz, 3 H)4.21 (br. s., 1H) 4.36- 403.2156 no)pyrimidin-4-yl)-4- 4.58 (m, 3 H)4.75 (br. s., 1H) 6.77 (d, (M + H)⁺, isopropyloxazolidin-2-one J = 8.71Hz, 2 H) 7.18 (d, J = 8.56 Hz, 2 H) Rt 2.30 7.87 (br. s., 1 H) 8.33 (d,J = 2.74 Hz, 1 H) min 543: (4S)-4-isopropyl-3-(2- (CD₃OD) 8.00-8.17 (m,1H), 7.71 (d, J = HRMS(A) ((1-(tetrahydrofuran-2- 7.04 Hz, 1H),4.78-4.85 (m, 1H), 4.41- m/z yl)ethyl)amino)pyrimidin-4- 4.55 (m, 2H),3.98-4.14 (m, 1H), 3.84- 321.1935 yl)oxazolidin-2-one 3.97 (m, 1H),3.67-3.82 (m, 1H), 2.55- (M + H)+, 2.70 (m, 1H), 1.86-2.13 (m, 3H),1.56- Rt 1.32 1.82 (m, 1H), 1.24-1.34 (m, 3H), 1.00- min 1.06 (m, 3H),0.91 (t, J = 6.06 Hz, 3H) 544: (S)-3-(2-((S)-1-(4- (400 MHz, DMSO) δ ppm0.54 (br. s., 3 H) HRMS(A) isobutoxy-3- 0.72 (br. s., 3 H) 0.96 (d, J =6.70 Hz, 6 H) m/z methylphenyl)ethylamino) 1.41 (d, J = 6.99 Hz, 3 H)1.89 (br. s., 1 H) 413.2561 pyrimidin-4-yl)-4- 1.99 (dt, J = 13.24, 6.61Hz, 1 H) 2.11 (s, 3 (M + H)+, isopropyloxazolidin-2-one H) 3.68 (d, J =6.41 Hz, 2 H) 4.31-4.41 (m, Rt 2.34 2 H) 4.62 (dd, J = 6.99, 3.72 Hz, 1H) 4.94 min (quin, J = 6.94 Hz, 1 H) 6.80 (d, J = 8.31 Hz, 1 H)7.00-7.13 (m, 2 H) 7.34 (d, J = 6.06 Hz, 1 H) 8.19 (d, J = 4.94 Hz, 1 H)8.42 (br. s., 1 H) 545: (S)-3-(2-((S)-1-(6-(1- ¹H NMR (400 MHz, CD₃OD) d0.65 (br. s., HRMS(A) ethoxycyclopropyl)pyridin- 3 H) 0.75 (br. s., 3 H)1.23 (t, J = 7.04 Hz, 3 m/z 3-yl)ethylamino)pyrimidin- H) 1.28-1.45 (m,4 H) 1.64 (d, J = 7.09 Hz, 412.2349 4-yl)-4- 3 H) 3.55 (q, J = 7.04 Hz,2 H) 4.36-4.43 (M + H)+, isopropyloxazolidin-2-one (m, 2 H) 4.70 (br.s., 1 H) 5.20-5.28 (m, 1 Rt 1.55 H) 7.66 (d, J = 8.41 Hz, 2 H) 8.04 (br.s., 1 min H) 8.16 (d, J = 6.41 Hz, 1 H) 546: (S)-3-(2-((S)-1-(4- ¹H NMR(400 MHz, DMSO) d ppm 0.54 HRMS isobutoxy-3- (br. s., 3 H) 0.72 (br. s.,3 H) 0.96 (d, m/z methylphenyl)ethylamino) J = 6.70 Hz, 6 H) 1.41 (d, J= 6.99 Hz, 3 H) 413.2561 pyrimidin-4-yl)-4- 1.89 (br. s., 1 H) 1.99 (dt,J = 13.24, 6.61 (M + H)+; isopropyloxazolidin-2-one Hz, 1 H) 2.11 (s, 3H) 3.68 (d, J = 6.41 Hz, 2 Rt 2.34 H) 4.31-4.41 (m, 2 H) 4.62 (dd, J =6.99, min. 3.72 Hz, 1 H) 4.94 (quin, J = 6.94 Hz, 1 H) 6.80 (d, J = 8.31Hz, 1 H) 7.00-7.13 (m, 2 H) 7.34 (d, J = 6.06 Hz, 1 H) 8.19 (d, J = 4.94Hz, 1 H) 8.42 (br. s., 1 H)

Example 547

A solution of(S)-3-(2-((S)-1-(4-(chloromethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one(75 mg, 0.2 mmol) and 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (25 mg,0.2 mmol) in DMSO (2 mL) was heated at 80° C. for 16 h. The reactionmixture was diluted with EtOAc (20 mL) and washed with water (20 mL).After separation, the aqueous phase was washed with EtOAc (2×15 mL).Combined organics were dried over Na2SO4, filtered and concentrated.Silica gel column chromatography (MeOH in CH₂Cl₂ 0 to 10%) provided(S)-3-(2-((S)-1-(4-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one(58 mg, white solid) in 62.8% yield.

¹H NMR (400 MHz, MeOD) δ 8.12 (d, J=6.0 Hz, 1H), 7.34 (d, J=5.9 Hz, 1H),7.33 (s, 4H), 6.99 (d, J=1.3 Hz, 1H), 6.89 (d, J=1.4 Hz, 1H), 5.07 (q,J=7.0 Hz, 1H), 4.68 (br s, 1H), 4.37-4.25 (m, 2H), 4.02 (t, J=5.5 Hz,2H), 3.72 (s, 2H), 3.63 (s, 2H), 2.90 (td, J=5.4, 2.6 Hz, 2H), 1.84 (brs, 1H), 1.51 (d, J=7.0 Hz, 3H), 0.72 (br s, 3H), 0.57 (br s, 3H); HRMSm/z 462.2606 (M+H)+.

The following compounds were prepared using methods similar to thosedescribed for the preparation of Example 205.

Example 548

(4S)-3-(2-((1S)-1-(4-(3,8-diazabicyclo[4.2.0]octan-3-ylmethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.

¹H NMR (400 MHz, MeOD) δ 8.12-8.08 (m, 1H), 7.37-7.22 (m, 5H), 5.10-5.01(m, 1H), 4.66 (br s, 1H), 4.37-4.23 (m, 2H), 3.92-3.89 (m, 1H),3.63-3.54 (m, 1H), 3.54-3.47 (m, 1H), 3.24-3.20 (m, 1H), 3.11-2.95 (m,1H), 2.95-2.73 (m, 1H), 0.2.67-2.59 (m, 2H), 2.49 (ddd, J=16.2, 12.8,5.3 Hz, 1H), 2.20-2.08 (m, 1H), 1.99-1.68 (m, 3H), 1.50 (d, J=7.0 Hz,3H), 0.72 (br s, 1H), 0.56 (br s, 1H); HRMS m/z 451.2810 (M+H)+.

Example 549

(S)-3-(2-((S)-1-(4-((4-aminopiperidin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

¹H NMR (400 MHz, MeOD) d 8.12 (d, J=5.8 Hz, 1H), 7.34 (d, J=5.8 Hz, 1H),7.27 (q, J=8.2 Hz, 4H), 5.05 (q, J=7.0 Hz, 1H), 4.67 (s, 1H), 4.38-4.25(m, 2H), 3.48 (s, 2H), 2.86 (br d, J=11.8 Hz, 2H), 2.71 (tt, J=10.9, 4.2Hz, 1H), 2.05 (tt, J=12.0, 2.5 Hz, 2H), 1.90-1.75 (m, 3H), 1.54-1.37 (m,5H), 0.72 (br s, 4H), 0.55 (br s, 3H); HRMS m/z 439.2805 (M+H)+.

The following compounds were prepared using methods similar to thosedescribed for the preparation of Example 210.

Example 550

(S)-3-(2-((S)-1-(4-((4-hydroxy-4-methylpiperidin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

¹H NMR (400 MHz, MeOD) δ 8.12 (d, J=5.7 Hz, 1H), 7.34 (d, J=5.9 Hz, 1H),7.27 (t, J=6.6 Hz, 4H), 5.06 (q, J=6.8 Hz, 1H), 4.67 (br s, 1H),4.37-4.25 (m, 2H), 3.51 (d, J=3.2 Hz, 2H), 2.52 (br s, 2H), 2.44 (br s,2H), 1.81 (br s, 1H), 1.59 (br s, 4H), 1.50 (d, J=7.0 Hz, 3H), 1.19 (s,3H), 0.72 (br s, 3H), 0.56 (br s, 3H); HRMS m/z 454.2816 (M+H)+.

Example 552

(S)-3-(2-((S)-1-(4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

¹H NMR (400 MHz, MeOD) δ 8.12 (d, J=5.8 Hz, 1H), 7.35 (d, J=5.8 Hz, 1H),7.28 (q, J=8.2 Hz, 4H), 5.06 (q, J=7.0 Hz, 1H), 4.67 (br s, 1H),4.39-4.25 (m, 2H), 3.55 (d, J=2.2 Hz, 2H), 2.56 (t, J=11.5 Hz, 2H),2.51-2.40 (m, 2H), 1.91-1.81 (m, 3H), 1.78-1.70 (m, 2H), 1.50 (d, J=7.0Hz, 3H), 0.71 (br s, 3H), 0.56 (br s, 3H); HRMS m/z 460.2537 (M+H)+.

Example 553

(S)-3-(2-((S)-1-(4-(4,7-diazaspiro[2.5]octan-7-ylmethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

¹H NMR (400 MHz, MeOD) δ 8.12 (d, J=5.8 Hz, 1H), 7.34 (d, J=5.8 Hz, 1H),7.32-7.24 (m, 4H), 5.06 (q, J=7.0 Hz, 1H), 4.68 (br s, 1H), 4.37-4.26(m, 2H), 3.49 (s, 2H), 2.89 (t, J=5.0 Hz, 2H), 2.47 (br s, 2H), 2.28 (brs, 2H), 1.86 (br s, 1H), 1.49 (d, J=7.0 Hz, 3H), 0.72 (br s, 3H),0.64-0.49 (m, 5H), 0.45 (t, J=3.2 Hz, 2H); HRMS m/z 451.2809 (M+H)+.

Example 554

(S)-3-(2-((S)-1-(4-(4,7-diazaspiro[2.5]octan-4-ylmethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

¹H NMR (400 MHz, MeOD) δ 8.11 (d, J=5.8 Hz, 1H), 7.33 (d, J=5.8 Hz, 1H),7.24 (q, J=8.3 Hz, 4H), 5.03 (q, J=7.0 Hz, 1H), 4.67 (br s, 1H),4.37-4.25 (m, 2H), 3.85 (s, 2H), 2.85-2.65 (m, 6H), 1.87 (br s, 1H),1.48 (d, J=7.0 Hz, 3H), 0.85-0.63 (m, 5H), 0.63-0.46 (m, 5H); HRMS m/z451.2810 (M+H)+.

Example 555

(S)-4-isopropyl-3-(2-((S)-1-(4-((3,3,4,4-tetrafluoropyrrolidin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one

HRMS m/z 482.2161 (M+H)+; RT=2.78 min.

Example 556

(S)-3-(2-((S)-1-(4-((4-acetylpiperazin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

HRMS m/z 467.2752 (M+H)+; RT=1.92 min.

Example 557

(S)-4,6-difluoro-N-(1-phenylethyl)pyrimidin-2-amine (48.8 mg, 0.21 mmol)was added to NaH (95%, 6.1 mg, 0.25 mmol, 1.2 equiv) in DMF (2 mL) at 0°C. After 5 min, (S)-4-isopropyl-2-oxazolidinone (27.9 mg, 0.22 mmol, 1.0equiv) was added. The reaction was stirred for 10 min at 0° C. and thenwarmed to room temperature. After 4 h, the reaction mixture was quenchedwith water and poured into dilute brine (1:1 sat. brine:water) andEtOAc. The aqueous phase was extracted with EtOAc and the combinedorganic layers were washed with diluted brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated to a pink oil. Purificationby reverse phase HPLC followed by lyopholization of the fractionscontaining product provided(S)-3-(6-fluoro-2-(((S)-1-phenylethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneas a white solid (22.5 mg TFA salt) in 31% yield. ¹H NMR (400 MHz,CD₃OD) δ 7.27-7.39 (m, 4H), 7.17-7.26 (m, 1H), 6.92 (s, 1H), 5.05 (q,J=7.04 Hz, 1H), 4.63 (br. s., 1H), 4.19-4.41 (m, 2H), 1.77 (br. s., 1H),1.51 (d, J=7.04 Hz, 3H), 0.44-0.78 (m, 6H); LCMS m/z 345.1 (M+H)⁺. R_(t)1.00 min; UPLC R_(t) 5.038 min.

The compounds in Table 17 were prepared using methods similar to thosedescribed for the preparation of Example 557.

TABLE 17

558

TABLE 18 Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 17. Example: Name ¹H NMR (400 MHz) δ ppm LCMS558: (S)-5,5-dimethyl-4- (CD₃OD) 8.06 (d, J = 5.8 Hz, 1 H), 7.43 (d,HRMS(A) phenyl-3-(2-((S)-1- J = 5.8 Hz, 1 H), 7.31-7.24 (m, 3 H), 7.19-m/z phenylethylamino)pyrim- 7.11 (m, 5 H), 7.01 (br s 2 H), 5.48 (s, 1389.1987 idin-4-yl)oxazolidin-2-one H), 4.86-4.80 (m, 1 H), 1.65 (s, 3H), 1.43 (M + H)⁺ (d, J = 7.0 Hz, 3 H), 0.98 (s, 3 H)

Example 559

A mixture of (R)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one(55.3 mg, 0.20 mmol), (S)-1-cyclopropylethylamine (40 μL, 0.26 mmol, 1.3equiv) and iPr₂Net (0.20 mL, 1.15 mmol, 5.7 equiv) in NMP (1 mL) washeated in the microwave at 180° C. for 20 min. The reaction mixture wasfiltered and purified by reverse phase HPLC to give(R)-3-(2-(((S)-1-cyclopropylethyl)amino)pyrimidin-4-yl)-4-phenyloxazolidin-2-oneas a white solid (8.8 mg) in 10% yield. ¹H NMR (400 MHz, CD₃OD) δ 7.72(d, J=6.26 Hz, 1H), 7.29-7.43 (m, 6H), 5.76 (dd, J=4.11, 8.80 Hz, 1H),4.28 (dd, J=4.30, 8.61 Hz, 1H), 3.06-3.19 (m, 1H), 1.39 (dd, J=3.52,6.65 Hz, 1H), 0.88-0.97 (m, 1H), 0.83 (br. s., 3H), 0.53-0.62 (m, 1H),0.50 (dt, J=4.11, 8.51 Hz, 1H), 0.33 (qd, J=4.78, 9.54 Hz, 1H), 0.26(td, J=4.60, 9.59 Hz, 1H); HRMS(A) m/z 325.1667 (M+H)⁺, Rt 1.54 min;UPLC 2.807 min.

The compounds in Table 19 were prepared using methods similar to thosedescribed for the preparation of Example 559.

TABLE 19

560

561

562

TABLE 20 Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 19. Example: Name ¹H NMR (400 MHz) δ ppm LCMS560: (S)-4-benzyl-3-(2- (CD₃OD) 8.13 (d, J = 7.04 Hz, 1H), 7.71 (d,HRMS(A) (((S)-1- J = 7.04 Hz, 1H), 7.22-7.38 (m, 5H), 5.11 m/zcyclopropylethyl)amino)pyrim- (tt, J = 3.03, 8.12 Hz, 1H), 4.23-4.53 (m,339.1822 idin-4-yl)oxazolidin-2- 2H), 3.08 (dd, J = 8.41, 13.50 Hz, 1H),(M + H)⁺, one 1.42 (d, J = 6.65 Hz, 3H), 1.04-1.23 (m, Rt 1.64 1H),0.47-0.73 (m, 2H), 0.17-0.47 (m, min 2H). 561: (S)-3-(5-fluoro-2-HRMS(A) (((S)-1-(3- m/z isopropylphenyl)ethyl)ami- 387.2203no)pyrimidin-4-yl)-4- (M + H)⁺, isopropyloxazolidin-2-one Rt 2.52 min562: (S)-3-(2-(((S)-1-(4- HRMS(A) chlorophenyl)ethyl)amino)- m/z5-fluoropyrimidin-4-yl)-4- 379.1341 isopropyloxazolidin-2-one (M + H)⁺,Rt 2.30 min

Example 563

A mixture of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(43.2 mg, 0.18 mmol), (1S)-1-[4-(2-Methylpropoxy)phenyl]ethan-1-amine(84.0 mg, 0.37 mmol, 2.0 equiv) and iPr₂Net (0.30 mL, 1.72 mmol, 4.7equiv) in NMP (1 mL) was heated at 105° C. for 24 h. The reactionmixture was filtered and purified by reverse phase HPLC to give(S)-3-(2-(((S)-1-(4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneas a white solid (5.3 mg, TFA salt) in 4% yield. ¹H NMR (400 MHz, CD₃OD)δ 7.68 (d, J=6.65 Hz, 1H), 7.25 (d, J=8.61 Hz, 2H), 6.90 (d, J=8.61 Hz,2H), 4.41 (d, J=5.87 Hz, 2H), 3.74 (d, J=6.26 Hz, 2H), 1.96-2.15 (m,1H), 1.58 (d, J=7.04 Hz, 3H), 1.03 (d, J=6.65 Hz, 6H); HRMS(A) m/z399.2399 (M+H)⁺, Rt 2.60 min; UPLC 4.223 min.

The compounds in Table 21 were prepared using methods similar to thosedescribed for the preparation of Example 563.

TABLE 21

564

565

TABLE 22 Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 21. Example: Name ¹H NMR (400 MHz) δ ppm LCMS564: (S)-3-(5-fluoro-2- HRMS(A) (((S)-1-(4- m/zisobutoxyphenyl)ethyl)ami- 417.2314 no)pyrimidin-4-yl)-4- (M + H)⁺,isopropyloxazolidin-2-one Rt 2.53 min 565: (S)-3-(5-fluoro-2- HRMS(A)(((S)-1-(2-fluoro-4-(1- m/z methyl-1H-pyrazol-4- 443.2012yl)phenyl)ethyl)amino)pyrim- (M + H)⁺, idin-4-yl)-4- Rt 1.92isopropyloxazolidin-2-one min

Example 566

To a microwave vial with stir bar was added(S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (24.96 mg,0.103 mmol) in DMSO (1653 μL). To this reaction mixture was added(S)-1-(2,3-difluorophenyl)ethanamine (40 mg, 0.207 mmol) and DIEA (144μL, 0.826 mmol). The vial capped and heated at 110° C. over the weekend.The solution was filtered, then purified by reverse phase HPLC. Productfractions combined, frozen and lyopholyzed to afford((S)-3-(2-((S)-1-(2,3-difluorophenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (10.2 mg, 0.021 mmol, 10.26%yield) as a TFA salt. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.59 (br. s., 3H)0.75 (br. s., 3H) 1.59 (d, J=6.99 Hz, 3H) 1.69 (br. s., 1H) 4.37 (d,J=5.67 Hz, 2H) 4.66 (br. s., 1H) 5.40 (d, J=7.38 Hz, 1H) 7.06-7.23 (m,3H) 7.70 (d, J=6.90 Hz, 1H) 8.14 (d, J=6.46 Hz, 1H); LCMS m/z 363.3(M+H)⁺, Rt 0.77 min.; HRMS(A) m/z 363.1642 (M+H)⁺, Rt 1.89 min.

Example 567

(S)-3-(2-(1-(2,3-difluorophenyl)ethylamino)-5-fluoropyrimidin-4-yl)oxazolidin-2-onewas prepared using a method similar to that described for thepreparation of Example 566. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.50 (d,J=7.04 Hz, 3H) 3.91 (br. s., 1H) 4.09-4.20 (m, 1H) 4.42-4.56 (m, 2H)5.26 (q, J=6.68 Hz, 1H) 6.99-7.12 (m, 2H) 7.16 (t, J=7.48 Hz, 1H) 8.13(d, J=3.37 Hz, 1H). HRMS(A) m/z 339.1075 (M+H)+, Rt 1.86 min.

Example 5682-fluoro-N-(trans-4-hydroxycyclohexyl)-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide

Step 1: Preparation of(S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoic acid

To (S)-4-(1-aminoethyl)-2-fluorobenzoic acid (900 mg, 4.10 mmol) wasadded, DCM (11 ml), Hunig's Base (2.147 ml, 12.29 mmol) andBOC-Anhydride (1.998 ml, 8.61 mmol). Then NMP (11.00 ml) was added tohelp solubility. The reaction was sonicated for 10 minutes and wasstirred at room temperature for 22 hours, followed by LCMS. The DCM wasmostly concentrated off. Then to the crude reaction was added 120 ml ofwater and basified with 10 ml of 5M NaOH. The basic aqueous solution wasextracted with 2×50 ml of (15% ethyl acetate in heptane) solution. Thento the basic aqueous solution (with the product) was added 150 ml ofethyl acetate and with stirring acidified with 2M aqueous HCl solutionto about pH 3. Then the ethyl acetate was extracted, saved and theacidic water extracted again with 100 ml of ethyl acetate. The organiclayers were combined and washed with 0.5M aqueous HCl solution 1×40 ml,with water 3×40 ml, and concentrated to constant mass to give 1104 mg of(S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoic acid, used asis. LCMS m/z BOC pattern of 269.0 (M+H-15 fragment) and weak 228.0(M+H-56 fragment) compared to expected 284.0 (M+H)⁺, Rt 0.72 min.

Step 2: Preparation of tert-butyl(S)-1-(3-fluoro-4-(trans-4-hydroxycyclohexylcarbamoyl)phenyl)ethylcarbamate

To (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoic acid (40.8mg, 0.144 mmol) was added NMP (0.5 ml), trans-4-aminocyclohexanol (41.5mg, 0.360 mmol), Hunig's Base (0.101 ml, 0.576 mmol) and HATU (110 mg,0.288 mmol) The reaction was stirred at room temperature for 6 hours,followed by LCMS. To the reaction was added 0.5 ml of NMP, filtered,purified by prep LC and lyophilized to give 33 mg of tert-butyl(S)-1-(3-fluoro-4-(trans-4-hydroxycyclohexylcarbamoyl)phenyl)ethylcarbamateas the TFA Salt. LCMS m/z 381.1 (M+H)+, Rt 0.70 min.

Step 3: Preparation of4-((S)-1-aminoethyl)-2-fluoro-N-(trans-4-hydroxycyclohexyl)benzamide

To tert-butyl(S)-1-(3-fluoro-4-(trans-4-hydroxycyclohexylcarbamoyl)phenyl)ethylcarbamate(33 mg, 0.087 mmol) was added, HCl 4M in Dioxane (2 mL, 8.00 mmol) andMeOH (0.2 ml). The reaction was stirred at room temperature for 1 hour,followed by LCMS. The solvent was concentrated off to residue to give4-((S)-1-aminoethyl)-2-fluoro-N-(trans-4-hydroxycyclohexyl)benzamide inquantitative yield (0.087 mmol) as HCl salt. LCMS m/z 281.1 (M+H)⁺, Rt0.33 min.

Step 4: Preparation of2-fluoro-N-(trans-4-hydroxycyclohexyl)-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide

To4-((S)-1-aminoethyl)-2-fluoro-N-((1r,4S)-4-hydroxycyclohexyl)benzamide(0.024 g, 0.087 mmol) was added(S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (0.034 g,0.139 mmol), DMSO (0.6 ml) and Hunig's Base (0.053 ml, 0.305 mmol). Thereaction was heated at 100-105° C. for 16 hours or until done by LCMS.The reaction was let cool, 0.5 ml of DMSO added, filtered, purified byprep LC and lyophilized to give 10.1 mg of2-fluoro-N-(trans-4-hydroxycyclohexyl)-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamideas the TFA Salt. LCMS m/z 486.2 (M+H)⁺, Rt 0.57 min.

¹H NMR (400 MHz, CD₃OD) δ ppm 8.13 (d, J=6.7 Hz, 1H), 7.70 (d, J=6.7 Hz,1H), 7.64 (t, J=7.8 Hz, 1H), 7.13-7.28 (m, 2H), 5.16 (br. s., 1H), 4.67(br. s., 1H), 4.37 (d, J=5.5 Hz, 2H), 3.82 (br. s., 1H), 3.53 (d, J=3.9Hz, 1H), 1.97 (dd, J=5.1, 3.1 Hz, 4H), 1.57 (d, J=7.0 Hz, 3H), 1.38 (t,J=8.6 Hz, 4H), 0.50-0.88 (m, 6H); HRMS(A) m/z 486.2523 (M+H)⁺.

Example 569(S)-3-(2-((S)-1-(6-(4-fluorophenoxy)pyridin-3-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

To (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (28 mg,0.116 mmol) was added (S)-1-(6-(4-fluorophenoxy)pyridin-3-yl)ethanamine(46.7 mg, 0.174 mmol), DMSO (0.6 ml) and Hunig's Base (0.071 ml, 0.406mmol). The reaction was heated at 105-110° C. for 24 hours or until doneby LCMS. The reaction was let cool, 0.5 ml of DMSO was added, filtered,purified by prep LC and lyophilized to give 7.1 mg of(S)-3-(2-((S)-1-(6-(4-fluorophenoxy)pyridin-3-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneas the TFA Salt. LCMS m/z 438.2 (M+H)⁺, Rt 0.82 min.

¹H NMR (400 MHz, CD₃OD) δ ppm 8.04 (d, J=6.3 Hz, 1H), 8.01 (d, J=2.0 Hz,1H), 7.73 (dd, J=8.6, 2.3 Hz, 1H), 7.53 (d, J=6.3 Hz, 1H), 6.94-7.10 (m,4H), 6.84 (d, J=8.6 Hz, 1H), 5.05 (d, J=7.0 Hz, 1H), 4.61 (d, J=3.9 Hz,1H), 4.28 (d, J=5.5 Hz, 2H), 1.49 (d, J=7.0 Hz, 3H), 0.51-0.78 (m, 6H);HRMS(A) m/z 438.1946 (M+H)⁺.

Example 570(S)-3-(2-((S)-1-(3-fluoro-4-(piperidine-1-carbonyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

To (S)-(4-(1-aminoethyl)-2-fluorophenyl)(piperidin-1-yl)methanone (0.019g, 0.076 mmol) was added(S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (0.028 g,0.114 mmol), NMP (0.5 ml) and Hunig's Base (0.033 ml, 0.190 mmol). Thereaction was heated at 105-110° C. for 16 hours or until done by LCMS.The reaction was let cool, 0.5 ml of NMP was added, filtered, purifiedby prep LC and lyophilized to give 4.0 mg of(S)-3-(2-((S)-1-(3-fluoro-4-(piperidine-1-carbonyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneas TFA Salt. LCMS m/z 456.1 (M+H)⁺, rt 0.74 min.

¹H NMR (400 MHz, CD₃OD) δ ppm 8.13 (d, J=6.7 Hz, 1H), 7.69 (d, J=7.0 Hz,1H), 7.30-7.38 (m, 1H), 7.23-7.28 (m, 1H), 7.20 (d, J=10.6 Hz, 1H), 5.18(br. s., 1H), 4.63-4.74 (m, 1H), 4.33-4.42 (m, 2H), 3.61-3.79 (m, 2H),1.61-1.76 (m, 5H), 1.57 (d, J=7.0 Hz, 3H), 1.51 (br. s., 2H), 0.77 (br.s., 3H), 0.62 (br. s., 3H); HRMS(A) m/z 456.2416 (M+H)⁺.

Example 571(S)-3-(5-fluoro-2-((S)-1-(3-fluoro-4-(piperidine-1-carbonyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

To (S)-(4-(1-aminoethyl)-2-fluorophenyl)(piperidin-1-yl)methanone (0.019g, 0.076 mmol) was added(S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(0.030 g, 0.114 mmol), NMP (0.5 ml) and Hunig's Base (0.033 ml, 0.190mmol). The reaction was heated at 105-110° C. for 8 hours or until doneby LCMS. The reaction was let cool, 0.5 ml of NMP added, filtered,purified by prep LC and lyophilized to give 4.5 mg of(S)-3-(5-fluoro-2-((S)-1-(3-fluoro-4-(piperidine-1-carbonyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-oneas TFA Salt. LCMS m/z 474.2 (M+H)⁺, Rt 0.91 min.

¹H NMR (400 MHz, CD₃OD) δ ppm 8.21 (d, J=2.7 Hz, 1H), 7.22-7.33 (m, 2H),7.17 (d, J=11.0 Hz, 1H), 4.97 (q, J=7.0 Hz, 1H), 4.59 (br. s., 1H), 4.47(t, J=8.8 Hz, 1H), 4.20-4.32 (m, 1H), 3.68 (br. s., 2H), 1.57-1.75 (m,5H), 1.48 (d, J=7.0 Hz, 5H), 0.69 (br. s., 3H), 0.62 (br. s., 3H);HRMS(A) m/z 474.2330 (M+H)⁺.

Example 572N-cyclohexyl-2-fluoro-4-((S)-1-(5-fluoro-4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide

To (S)-4-(1-aminoethyl)-N-cyclohexyl-2-fluorobenzamide (16 mg, 0.061mmol) was added(S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one(31.4 mg, 0.121 mmol), NMP (0.5 ml) and Hunig's Base (0.032 ml, 0.182mmol). The reaction was heated at 125° C. for 4 hours or until done byLCMS. The reaction was let cool, 0.5 ml of NMP added, filtered, purifiedby prep LC and lyophilized to give 2.5 mg ofN-cyclohexyl-2-fluoro-4-((S)-1-(5-fluoro-4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamideas the TFA Salt. LCMS m/z 488.2 (M+H)⁺, Rt 0.99 min.

¹H NMR (400 MHz, CD₃OD) δ ppm 8.21 (br. s., 1H), 7.62 (t, J=7.8 Hz, 1H),7.24 (dd, J=8.0, 1.4 Hz, 1H), 7.16 (d, J=12.1 Hz, 1H), 4.39-4.54 (m,2H), 4.23 (t, J=7.2 Hz, 1H), 3.83 (t, J=10.4 Hz, 1H), 1.86-1.97 (m, 2H),1.76 (d, J=12.9 Hz, 2H), 1.64 (d, J=12.9 Hz, 1H), 1.48 (d, J=7.0 Hz,3H), 1.12-1.42 (m, 6H), 0.61 (br. s., 6H); HRMS(A) m/z 488.2484 (M+H)⁺

Example 573N-cyclohexyl-2-fluoro-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide

To (S)-4-(1-aminoethyl)-N-cyclohexyl-2-fluorobenzamide (16 mg, 0.061mmol) was added(S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (29.3 mg,0.121 mmol), NMP (0.5 ml) and Hunig's Base (0.032 ml, 0.182 mmol). Thereaction was heated at 125° C. for 4 hours or until done by LCMS. Thereaction was let cool, 0.5 ml of NMP added, filtered, purified by prepLC and lyophilized to give 5.6 mg ofN-cyclohexyl-2-fluoro-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamideas the TFA Salt. LCMS m/z 470.2 (M+H)+, Rt 0.83 min.

¹H NMR (400 MHz, CD₃OD) δ ppm 8.12 (br. s., 1H), 7.57-7.73 (m, 2H),7.13-7.27 (m, 2H), 5.15 (br. s., 1H), 4.66 (br. s., 1H), 4.36 (d, J=5.5Hz, 2H), 3.76-3.94 (m, 1H), 1.87-1.99 (m, 2H), 1.77 (d, J=12.9 Hz, 2H),1.65 (d, J=13.7 Hz, 1H), 1.57 (d, J=7.0 Hz, 3H), 1.12-1.50 (m, 6H), 0.73(br. s., 3H), 0.62 (br. s., 3H); HRMS(A) m/z 470.2572 (M+H)⁺

Example 574(S)-4-Isopropyl-3-(2-(((S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

To the solution of(S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (43 mg, 0.169mmol) in NMP (0.7 mL) was added(S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethanamine (41 mg, 0.169 mmol) andDIEA (88 μL, 0.507 mmol). The brown reaction mixture was stirred at 110°C. for 2 days. The reaction mixture was diluted with ethyl acetate andaqueous sodium bicarbonate solution. The separated organic layer waswashed with saturated aqueous sodium bicarbonate solution, water andbrine. The organic phase was dried over sodium sulfate, filtered off andconcentrated under reduced pressure. The residue was purified by reversephase column chromatography [C-18] to provide(S)-4-isopropyl-3-(2-(((S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(7 mg) as its trifluoroacetic acid salt.

MS m/z 421.3 (M+H)⁺, Rt 0.68 min.

HRMS(A) m/z 421.1996 (M+H)⁺, Rt 1.54 min.

Example 5754-Phenyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)-1,8-dioxa-3-azaspiro[4.5]decan-2-one

A mixture of crude3-(2-chloropyrimidin-4-yl)-4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one(330 mg, 0.954 mmol), (S)-1-phenylethanamine (810 mg, 6.68 mmol),Hunig's base (1.17 mL, 6.68 mmol) in DMA (3.5 mL) was heated in a sealedtube at 80° C. for ˜16 hours. The mixture was allowed to cool to roomtemperature, diluted with DMSO and purified by reverse phase HPLC.Selected fractions were combined and lyophilized, providing4-phenyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)-1,8-dioxa-3-azaspiro[4.5]decan-2-oneas its trifluoroacetic acid salt as a white solid. LCMS m/z 431.2(M+H)⁺, Rt 0.83 min.

The solid was dissolved in ethyl acetate/saturated aqueous NaHCO₃solution. The separated organic layer was washed with saturated aqueousNaHCO₃ solution (2×), brine, dried over sodium sulfate, filtered off andconcentrated under reduced pressure providing4-phenyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)-1,8-dioxa-3-azaspiro[4.5]decan-2-one(120 mg).

Examples 576 & 577(S)-4-phenyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)-1,8-dioxa-3-azaspiro[4.5]decan-2-oneand(R)-4-phenyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)-1,8-dioxa-3-azaspiro[4.5]decan-2-one

120 mg of4-phenyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)-1,8-dioxa-3-azaspiro[4.5]decan-2-onewere dissolved in EtOH (10 mL).

Analytical Separation:

Column: CHIRALPAK AD-H (5 um) 100×4.6 mm (Daicel Chemical Industries,LTD.).

Solvent: n-heptane:ethyl alcohol=70:30

Flow rate: 1.0 mL/min; detection: UV=220 nm.

Fraction 1: Retention time: 5.84 min.

Fraction 2: Retention time: 10.18 min.

Preparative Separation:

Column: CHIRALPAK AD-prep (10 um) 2×25 cm.

Solvent: n-heptane:ethyl alcohol=70:30

Flow rate: 20 mL/min; 530 psi; injection: 4 mL; detection: UV=210 nm.

Fractions were concentrated under reduce pressure. The residue wasdissolved in acetonitrile and filtered through a syringe filter, dilutedwith water and lyophilized.

Example 576: Peak 1: white powder. Yield: 52.0 mg; de=99% (UV, 220 nm).

LCMS m/z 431.3 (M+H)⁺, Rt 0.81 min.

Example 577: Peak 2: white powder. Yield: 47.8 mg; de=99% (UV, 220 nm).

LCMS m/z 431.3 (M+H)⁺, Rt 0.81 min.

Examples 578 and 579

(R)-8-phenyl-7-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)-2,5-dioxa-7-azaspiro[3.4]octan-6-oneand(S)-8-phenyl-7-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)-2,5-dioxa-7-azaspiro[3.4]octan-6-onewere prepared using methods similar to those described for thepreparation of Example 576 & 577.

TABLE 23 Chiral column Chiral column for for quality Example separation/control/ Retention No. Structure conditions conditions time 578 (Peak 1)

AD column; 56 mg/ 6 mL EtOH; heptane:EtOH 75:25; 20 mL/min, 400 psi AD-Hcolumn; heptane:EtOH 75:25; 1 mL/min 5.4 min 579 (Peak 2) AD-H column:heptane:EtOH 75:25; 1 mL/min 8.9 min

The compounds in Table 24 were prepared using methods similar to thosedescribed for the preparation of Example 569

TABLE 24

580

581

582

TABLE 25 Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 24. Example: Name ¹H NMR (400 MHz) δ ppm LCMS580: (S)-3-(5-fluoro-2-((S)- (CD₃OD) 0.46-0.69 (m, 6 H) 0.81-0.91HRMS(A) 1-(2-fluoro-4- (m, 1 H) 1.53 (d, J = 3.00 Hz, 3 H) 4.21- m/z(trifluoromethyl)phenyl)eth- 4.29 (m, 1 H) 4.43-4.53 (m, 2 H) 5.25 (m,431.1516 ylamino)pyrimidin-4-yl)-4- J = 7.00, 7.00, 7.00 Hz, 1 H) 7.43(m, (M + H)+; isopropyloxazolidin-2-one J = 7.40 Hz, 2 H) 7.52-7.59 (m,1 H) 8.21- Rt-2.40 8.27 (m, 1 H) min 581: (S)-4-isopropyl-3-(2- (CD₃OD)0.63-1.00 (m, 7 H) 4.37-4.49 HRMS(A) (4- (m, 2 H) 4.58-4.65 (m, 1 H)4.66-4.78 m/z phenoxybenzylamino)pyrim- (m, 2 H) 6.95-7.02 (m, 4 H)7.10-7.16 405.1935 idin-4-yl)oxazolidin-2- (m, 1 H) 7.32-7.40 (m, 4 H)7.75 (d, (M + H)+; one J = 7.04 Hz, 1 H) 8.16 (d, J = 6.65 Hz, 1 H)Rt-2.02 min 582: (4S)-4-isopropyl-3-(2- HRMS(A) (1-(4,5,6,7- m/ztetrahydrobenzo[d]thiazol- 388.1814 2-yl)ethylamino)pyrimidin- (M + H)+;4-yl)oxazolidin-2-one Rt- 1.82/1.88 min

Examples 583 & 584(S)-4-isopropyl-3-(2-((R)-1,1,1-trifluoropropan-2-ylamino)pyrimidin-4-yl)oxazolidin-2-one(S)-4-isopropyl-3-(2-((S)-1,1,1-trifluoropropan-2-ylamino)pyrimidin-4-yl)oxazolidin-2-one

To a solution of(S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (40 mg, 0.166mmol) in 2-butanol was added 1,1,1-trifluoropropan-2-amine (74.9 mg,0.662 mmol) and para-toluenesulfonic acid monohydrate (74.9 mg, 0.662mmol). The mixture was heated under argon in a sealed vial for ˜7 daysat 115° C. Independently, to a solution of(S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (100 mg,0.414 mmol) in 2-butanol was added 1,1,1-trifluoropropan-2-amine (187mg, 1.655 mmol) and para-toluenesulfonic acid monohydrate (157 mg, 0.828mmol). The mixture was heated under argon in a sealed vial at 115° C.for ˜4 days. The two reaction mixtures was combined and concentratedunder reduced pressure. The residue was diluted with DMSO and water (˜10vol. % of DMSO), filtered through a syringe filter and purified byreverse phase HPLC. Selected fractions were collected and lyophilizedproviding two isomers as white solids as their trifluoroacetic acidsalts.

1st Peak 583: Yield: 29.1 mg.

¹H NMR (400 MHz, CD₃OD) δ ppm 0.90 (d, J=7.04 Hz, 3H) 0.98-1.02 (m, 3H)1.45 (d, J=7.04 Hz, 3H) 2.59 (dtd, J=13.89, 6.95, 6.95, 3.52 Hz, 1H)4.43-4.47 (m, 2H) 4.76-4.83 (m, 2H) 7.70 (d, J=5.87 Hz, 1H) 8.20 (d,J=6.26 Hz, 1H)

LCMS m/z 319.3 (M+H)⁺, Rt 0.73 min. HRMS(A) m/z 319.1391 (M+H)+, Rt 1.89min

2nd Peak 584: Yield: 38.5 mg.

¹H NMR (400 MHz, CD₃OD) δ ppm 0.87 (d, J=7.04 Hz, 3H) 0.98 (d, J=7.04Hz, 3H) 1.45 (d, J=7.04 Hz, 3H) 2.48-2.60 (m, 1H) 4.40-4.49 (m, 2H)4.88-4.95 (m, 2H) 7.69 (d, J=5.87 Hz, 1H) 8.20 (d, J=6.65 Hz, 1H)

LCMS m/z 319.3 (M+H)⁺, Rt 0.73 min. HRMS(A) m/z 319.1385 (M+H)+, Rt 1.88min

Example 585(4S)-4-phenyl-3-(2-(1,1,1-trifluoropropan-2-ylamino)pyrimidin-4-yl)oxazolidin-2-one

A mixture of (S)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one (40mg, 0.145 mmol), 1,1,1-trifluoropropan-2-amine (82 mg, 0.725 mmol),Hunig's Base (0.038 mL, 0.218 mmol) in DMSO (0.4 mL) was heated underargon at 115° C. for ˜3 days. Then mixture was allowed to cool to roomtemperature. The mixture was diluted with DMSO and water (˜10 vol. % ofDMSO), filtered through a syringe filter and purified by reverse phaseHPLC. Selected fractions were collected and lyophilized providing(45)-4-phenyl-3-(2-(1,1,1-trifluoropropan-2-ylamino)pyrimidin-4-yl)oxazolidin-2-one(ratio of two isomers: 7/3) as white solid as its trifluoroacetic acidsalt. LCMS m/z 353.2 (M+H)+, Rt 0.78 min. HRMS(A) m/z 353.1231 (M+H)+,Rt 1.92/1.96 min.

Example 586(S)-3-(2-((S)-1-cyclopropylethylamino)-5-fluoropyrimidin-4-yl)-4-phenyloxazolidin-2-one

A mixture of(S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-phenyloxazolidin-2-one (40 mg,0.136 mmol), (S)-1-cyclopropylethanamine (34.8 mg, 0.409 mmol), Hunig'sBase (0.119 mL, 0.681 mmol) in DMSO (0.4 mL) was heated under argon at105-115° C. for ˜18 hrs (alternative: 120-135° C. for ˜90 min). Thenmixture was allowed to cool to room temperature. The mixture was dilutedwith DMSO and water (˜10 vol. % of DMSO), filtered through a syringefilter and purified by reverse phase HPLC. Selected fractions werecollected and lyophilized providing(S)-3-(2-((S)-1-cyclopropylethylamino)-5-fluoropyrimidin-4-yl)-4-phenyloxazolidin-2-one(26 mg) as a white solid as its trifluoroacetic acid salt.

¹H NMR (400 MHz, CD₃OD) δ ppm −0.14-0.05 (m, 1H) 0.01-0.08 (m, 1H)0.23-0.31 (m, 1H) 0.36-0.44 (m, 1H) 0.78-0.86 (m, 1H) 1.19 (d, J=6.65Hz, 3H) 3.05-3.14 (m, 1H) 4.25-4.32 (m, 1H) 4.89-4.90 (m, 1H) 5.77 (t,J=8.61 Hz, 1H) 7.32-7.39 (m, 5H) 8.15 (d, J=3.52 Hz, 1H).

LCMS m/z 343.1 (M+H)⁺, Rt 0.88 min. HRMS(A) m/z 343.1577 (M+H)⁺, Rt 2.09min

The compounds in Table 26 were prepared using methods similar to thosedescribed for the preparation of Example 586.

TABLE 26

587

588

589

TABLE 27 Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 26. Example: Name ¹H NMR (400 MHz) δ ppm LCMS587: (S)-3-(2-((S)-1- (CD₃OD) −0.55-−0.27 (m, 1 H), −0.01 (m, MS m/zcyclopropylethylami- J = 9.00, 4.30 Hz, 1 H), 0.12-0.32 (m, 1 H) 325.2no)pyrimidin-4-yl)-4- 0.35-0.50 (m, 1 H) 0.64-0.93 (m, 1 H) (M + H)+;phenyloxazolidin-2-one 1.28 (d, J = 1.00 Hz, 3 H) 2.77-3.00 (m, 1 Rt- H)4.26 (dd, J = 1.00 Hz, 1 H) 4.76-4.95 0.77 min. (m, 1-2 H; overlay withsolvent) 5.75 (dd, HRMS(A) J = 1.00 Hz, 1 H) 7.17-7.52 (m, 5 H) 7.78 m/z(d, J = 1.00 Hz, 1 H) 8.08 (d, J = 7.04 Hz, 1 325.1664 H) (M + H)+;Rt-1.53 min 588: (S)-4-(biphenyl-4-yl)- (CD₃OD) 0.01 (m, J = 4.30 Hz, 1H) 0.14- MS m/z 3-(2-((S)-1- 0.26 (m, 1 H) 0.33-0.45 (m, 1 H) 0.73-401.3 (M + cyclopropylethylamino)pyrim- 0.85 (m, 1 H) 1.28 (d, J = 6.65Hz, 3 H) 2.91- H)+; Rt- idin-4-yl)oxazolidin-2- 3.02 (m, 1 H) 4.32 (dd,J = 9.00, 4.30 Hz, 1 0.89 min. one H) 4.89-4.96 (m, 1 H) 5.81 (dd, J =9.00, HRMS(A) 4.30 Hz, 1 H) 7.34-7.42 (m, 3 H) 7.45 (t, m/z J = 7.63 Hz,2 H) 7.59-7.64 (m, 2 H) 7.67 401.1988 (m, J = 8.20 Hz, 2 H) 7.79 (d, J =7.04 Hz, 1 (M + H)+; H) 8.10 (d, J = 7.04 Hz, 1 H) Rt-1.89 min 589:(S)-3-(2-(1- (CD₃OD) 0.17-0.24 (m, 1 H) 0.31 (dq, HRMS(A)cyclopropylethylamino)-5- J = 9.34, 4.71 Hz, 1 H) 0.41-0.55 (m, 2 H) m/zfluoropyrimidin-4-yl)- 0.93-1.04 (m, 1 H) 1.26 (d, J = 6.65 Hz, 3464.1125 4,4,5,5- H) 1.42 (s, 6 H) 1.49 (s, 6 H) 3.34-3.42 (M + H)⁺,tetramethyloxazolidin-2- (m, 1 H) 8.17 (d, J = 3.13 Hz, 1 H) MS m/z Rt2.28 one 323.6 (M + H)+; Rt-0.89 min. HRMS m/z mm 323.1891 (M + H)+;Rt-2.10 min

The compounds in Table 28 were prepared using methods similar to thosedescribed for the preparation of Example 568

TABLE 28

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

TABLE 29 Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 28. Example: Name ¹H NMR (400 MHz) δ ppm LCMS590: N-cyclopentyl-2- (CD₃OD) 8.14 (d, J = 6.3 Hz, 1H), 7.72 (d, HRMS(A)fluoro-4-((S)-1-(4-((S)-4- J = 7.0 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H),m/z (M + isopropyl-2-oxooxazolidin- 7.13-7.31 (m, 2H), 5.17 (br. s.,1H), 4.67 H)+ 3-yl)pyrimidin-2- (br. s., 1H), 4.34-4.41 (m, 2H),4.24-4.33 456.2422 ylamino)ethyl)benzamide (m, 1H), 1.99 (dt, J = 11.7,5.9 Hz, 2H), 1.73 (d, J = 6.7 Hz, 2H), 1.49-1.66 (m, 8H), 0.74 (br. s.,3H), 0.61 (br. s., 3H) 591: N-(4,4- (CD₃OD) 8.14 (d, J = 6.3 Hz, 1H),7.70 (d, HRMS(A) difluorocyclohexyl)-2- J = 7.0 Hz, 1H), 7.64 (t, J =7.8 Hz, 1H), m/z (M + fluoro-4-((S)-1-(4-((S)-4- 7.12-7.32 (m, 2H), 5.16(br. s., 1H), 4.67 H)+ isopropyl-2-oxooxazolidin- (br. s., 1H), 4.37 (d,J = 5.9 Hz, 2H), 4.00 506.2388 3-yl)pyrimidin-2- (t, J = 10.0 Hz, 1H),1.82-2.13 (m, 6H), ylamino)ethyl)benzamide 1.61-1.77 (m, 2H), 1.57 (d, J= 7.0 Hz, 3H), 0.73 (br. s., 3H), 0.61 (br. s., 3H) 592:2-fluoro-4-((S)-1-(4- (CD₃OD) 8.13 (d, J = 5.9 Hz, 1H), 7.58- HRMS(A)((S)-4-isopropyl-2- 7.71 (m, 2H), 7.13-7.29 (m, 2H), 5.16 (br. m/z (M +oxooxazolidin-3- s., 1H), 4.67 (br. s., 1H), 4.36 (d, J = 5.5 H)+yl)pyrimidin-2- Hz, 2H), 4.01-4.16 (m, 1H), 3.94 (d, J = 472.2366ylamino)ethyl)-N- 11.3 Hz, 2H), 3.50 (td, J = 11.7, 2.0 Hz,(tetrahydro-2H-pyran-4- 2H), 1.82-1.94 (m, 2H), 1.59-1.69 (m,yl)benzamide 2H), 1.57 (d, J = 7.0 Hz, 3H), 0.73 (br. s., 3H), 0.61 (br.s., 3H) 593: 2-fluoro-N-((1R,2S)- (CD₃OD) 8.14 (d, J = 6.3 Hz, 1H), 7.83(t, HRMS(A) 2-hydroxycyclohexyl)-4- J = 7.8 Hz, 1H), 7.69 (d, J = 7.0Hz, 1H), m/z (M + ((S)-1-(4-((S)-4-isopropyl- 7.14-7.36 (m, 2H), 5.15(d, J = 6.3 Hz, H)+ 2-oxooxazolidin-3- 1H), 4.65 (br. s., 1H), 4.36 (d,J = 5.5 Hz, 486.2526 yl)pyrimidin-2- 2H), 3.96-4.05 (m, 1H), 3.94 (d, J= 2.3 ylamino)ethyl)benzamide Hz, 1H), 1.79 (dd, J = 10.4, 4.5 Hz, 1H),1.69 (d, J = 5.9 Hz, 4H), 1.54-1.64 (m, 5H), 1.28-1.48 (m, 2H), 0.70(br. s., 3H), 0.60 (br. s., 3H) 594: N-(1,1- (CD₃OD) 8.14 (d, J = 6.3Hz, 1H), 7.69 (d, HRMS(A) dioxidotetrahydro-2H- J = 7.0 Hz, 1H), 7.64(t, J = 7.6 Hz, 1H), m/z (M + thiopyran-4-yl)-2-fluoro-4- 7.15-7.31 (m,2H), 5.16 (br. s., 1H), 4.67 H)+ ((S)-1-((4-((S)-4-isopropyl- (br. s.,1H), 4.36 (d, J = 5.9 Hz, 2H), 4.13- 520.203 2-oxooxazolidin-3- 4.27 (m,1H), 3.08 (d, J = 13.7 Hz, 2H), yl)pyrimidin-2- 2.25-2.36 (m, 2H),2.07-2.24 (m, 2H), yl)amino)ethyl)benzamide 1.57 (d, J = 7.0 Hz, 3H),0.73 (br. s., 3H), 0.61 (br. s., 3H) 595: 2-fluoro-N-((1R,2R)- (CD₃OD)8.13 (d, J = 6.3 Hz, 1H), 7.63- HRMS(A) 2-hydroxycyclohexyl)-4- 7.78 (m,2H), 7.14-7.30 (m, 2H), 5.15 (br. m/z (M + ((S)-1-(4-((S)-4-isopropyl-s., 1H), 4.67 (br. s., 1H), 4.36 (d, J = 5.5 H)+ 2-oxooxazolidin-3- Hz,2H), 3.67-3.83 (m, 1H), 3.38-3.51 486.2521 yl)pyrimidin-2- (m, 1H), 2.01(d, J = 9.0 Hz, 2H), 1.64- ylamino)ethyl)benzamide 1.81 (m, 3H), 1.57(d, J = 7.0 Hz, 3H), 1.17- 1.46 (m, 4H), 0.74 (br. s., 3H), 0.61 (br.s., 3H) 596: 2-fluoro-4-((S)-1-(4- (CD₃OD) 8.14 (d, J = 6.7 Hz, 1 H),7.76 (d, HRMS(A) ((S)-4-isopropyl-2- J = 7.4 Hz, 1H), 7.32-7.42 (m, 1H),7.17- m/z (M + oxooxazolidin-3- 7.31 (m, 2H), 5.22 (br. s., 1H),4.60-4.76 H)+ yl)pyrimidin-2- (m, 2H), 4.33-4.44 (m, 2H), 4.02 (dd, J =486.2528 ylamino)ethyl)-N-methyl- 11.3, 4.3 Hz, 1H), 3.91 (d, J = 8.6Hz, 1H), N-(tetrahydro-2H-pyran-4- 3.45-3.65 (m, 2H), 3.07-3.21 (m, 1H),yl)benzamide 2.99 (s, 1H), 2.80 (s, 2H), 1.81-2.05 (m, 3H), 1.52-1.71(m, 5H), 0.78 (br. s., 3H), 0.63 (br. s., 3H) 597: 2-fluoro-4-((S)-1-(4-(CD₃OD) 8.14 (d, J = 7.0 Hz, 1H), 7.75 (d, HRMS(A) ((S)-4-isopropyl-2- J= 7.0 Hz, 1H), 7.32-7.43 (m, 1H), 7.13- m/z (M + oxooxazolidin-3- 7.31(m, 2H), 5.20 (br. s., 1H), 4.70 (br. s., H)+ yl)pyrimidin-2- 1H),4.33-4.45 (m, 2H), 3.09 (s, 3H), 2.92 416.2106 ylamino)ethyl)-N,N- (d, J= 0.8 Hz, 3H), 1.76 (br. s., 1H), 1.59 dimethylbenzamide (d, J = 7.0 Hz,3H), 0.78 (br. s., 3H), 0.62 (br. s., 3H) 598: (S)-3-(2-((S)-1-(3-(CD₃OD) 8.14 (d, J = 6.7 Hz, 1H), 7.73 (d, HRMS(A)fluoro-4-(morpholine-4- J = 6.7 Hz, 1H), 7.35-7.43 (m, 1H), 7.28 m/z(M + carbonyl)phenyl)ethylami- (d, J = 7.8 Hz, 1H), 7.22 (d, J = 10.6Hz, H)+ no)pyrimidin-4-yl)-4- 1H), 5.18 (br. s., 1H), 4.69 (br. s., 1H),4.30- 458.2209 isopropyloxazolidin-2-one 4.42 (m, 2H), 3.73 (d, J = 3.1Hz, 4H), 3.59 (t, J = 4.7 Hz, 2H), 1.58 (d, J = 7.0 Hz, 3H), 0.76 (br.s., 3H), 0.62 (br. s., 3H) 599: (S)-3-(2-((S)-1-(3- (CD₃OD) 8.14 (d, J =6.7 Hz, 1H), 7.76 (d, HRMS(A) fluoro-4-((R)-3- J = 7.0 Hz, 1H), 7.36 (d,J = 6.7 Hz, 1H), m/z (M + methylmorpholine-4- 7.14-7.31 (m, 2H), 5.20(br. s., 1H), 4.70 H)+ carbonyl)phenyl)ethylami- (br. s., 1H), 4.65 (br.s., 1H), 4.34-4.45 472.2366 no)pyrimidin-4-yl)-4- (m, 2H), 4.29 (d, J =13.3 Hz, 1H), 3.96 (d, isopropyloxazolidin-2-one J = 10.6 Hz, 1H), 3.75(d, J = 11.3 Hz, 1H), 3.51-3.67 (m, 2H), 3.43-3.51 (m, 1H), 3.07-3.19(m, 1H), 1.76 (br. s., 1H), 1.59 (d, J = 7.0 Hz, 3H), 1.36 (d, J = 6.7Hz, 2H), 1.28 (br. s., 1H), 0.77 (br. s., 3H), 0.62 (br. s., 3H) 600:(S)-3-(2-((S)-1-(3- (CD₃OD) 8.14 (d, J = 6.7 Hz, 1H), 7.73 (d, HRMS(A)fluoro-4-(4- J = 7.0 Hz, 1H), 7.31-7.40 (m, 1H), 7.16- m/z (M +hydroxypiperidine-1- 7.29 (m, 2H), 5.18 (br. s., 1H), 4.70 (br. s., H)+carbonyl)phenyl)ethylami- 1H), 4.31-4.45 (m, 2H), 4.16 (dd, J = 472.2369no)pyrimidin-4-yl)-4- 12.9, 5.5 Hz, 1H), 3.87 (br. s., 1H), 3.48 (d,isopropyloxazolidin-2-one J = 14.1 Hz, 1H), 3.35 (d, J = 3.5 Hz, 1H),3.05-3.22 (m, 1H), 1.85-1.98 (m, 1 H), 1.70-1.83 (m, 2H), 1.58 (d, J =7.0 Hz, 3H), 1.49-1.55 (m, 1H), 1.43 (br. s., 1H), 0.76 (br. s., 3H),0.62 (br. s., 3H) 601: (S)-3-(2-((S)-1-(3- (CD₃OD) 8.13 (d, J = 6.7 Hz,1H), 7.70 (d, HRMS(A) fluoro-4-(4- J = 6.7 Hz, 1H), 7.31-7.41 (m, 1H),7.26 m/z (M + methoxypiperidine-1- (d, J = 7.8 Hz, 1H), 7.21 (d, J =10.6 Hz, H)+ carbonyl)phenyl)ethylami- 1H), 5.17 (br. s., 1H), 4.69 (br.s., 1H), 4.33- 486.2523 no)pyrimidin-4-yl)-4- 4.42 (m, 2H), 3.98 (dd, J= 10.8, 6.5 Hz, isopropyloxazolidin-2-one 1H), 3.40-3.60 (m, 3H), 3.34(s, 3H), 3.18 (d, J = 8.6 Hz, 1H), 1.88-2.03 (m, 1H), 1.79 (br. s., 1H),1.62 (br. s., 1H), 1.58 (d, J = 7.0 Hz, 3H), 1.49 (br. s., 1H), 0.76(br. s., 3H), 0.62 (br. s., 3H) 602: (S)-3-(2-((S)-1-(3- (CD₃OD) 8.14(d, J = 6.7 Hz, 1H), 7.73 (d, HRMS(A) fluoro-4-(4- J = 7.0 Hz, 1H),7.34-7.44 (m, 1H), 7.16- m/z (M + fluoropiperidine-1- 7.31 (m, 2H), 5.18(br. s., 1H), 4.93 (br. s., H)+ carbonyl)phenyl)ethylami- 1H), 4.70 (br.s., 1H), 4.29-4.43 (m, 2H), 474.2324 no)pyrimidin-4-yl)-4- 3.91 (d, J =11.3 Hz, 1H), 3.70 (br. s., 1H), isopropyloxazolidin-2-one 3.40-3.53 (m,1H), 1.93-2.06 (m, 1H), 1.83-1.93 (m, 2H), 1.77 (dd, J = 10.2, 4.7 Hz,2H), 1.58 (d, J = 7.0 Hz, 3H), 0.76 (br. s., 3H), 0.62 (br. s., 3H) 603:(S)-3-(2-((S)-1-(3- (CD₃OD) 8.13 (d, J = 6.7 Hz, 1H), 7.72 (d, HRMS(A)fluoro-4-((R)-3- J = 7.0 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), m/z (M +hydroxypiperidine-1- 7.14-7.30 (m, 2H), 5.19 (br. s., 1H), 4.70 H)+carbonyl)phenyl)ethylami- (br. s., 1H), 4.30-4.44 (m, 2H), 3.71 (br.472.2362 no)pyrimidin-4-yl)-4- s., 1H), 3.38-3.52 (m, 1H), 3.08-3.19 (m,isopropyloxazolidin-2-one 1H), 3.02 (br. s., 1H), 1.96 (br. s, 1H), 1.87(br. s., 1H), 1.66-1.81 (m, 1H), 1.49-1.62 (m, 5H), 1.43 (br. s., 1H),0.78 (br. s., 3H), 0.63 (br. s., 3H) 604: (S)-3-(2-((S)-1-(3- (CD₃OD)8.13 (d, J = 6.3 Hz, 1H), 7.71 (d, HRMS(A) fluoro-4-(pyrrolidine-1- J =7.0 Hz, 1H), 7.34-7.43 (m, 1H), 7.14- m/z (M + carbonyl)phenyl)ethylami-7.30 (m, 2H), 5.18 (br. s., 1H), 4.70 (br. s., H)+ no)pyrimidin-4-yl)-4-1H), 4.28-4.43 (m, 2H), 3.57 (t, J = 6.8 442.2263isopropyloxazolidin-2-one Hz, 2H), 1.93-2.07 (m, 2H), 1.83-1.93 (m, 2H),1.58 (d, J = 7.0 Hz, 3H), 0.77 (br. s., 3H), 0.63 (br. s., 3H)

Biological Data Mutant IDH1 Biochemical Assay: LC-MS Detection of 2-HG.

Mutant IDH1 R132H catalytic activity was monitored using thequantitative liquid chromatography/mass spectrometry (LC-MS) detectionof 2-HG, a product of the NADPH-dependent alpha-KG reduction reaction.

More specifically, the biochemical reactions were performed at roomtemperature in 384-well Greiner flat-bottom plates (Costar, Cat. No.781201) using a final reaction volume of 30 μL and the following assaybuffer conditions: 50 mM HEPES pH 7.4, 10 mM MgCl₂, 50 mM KCl, 1 mM DTT,0.02% BSA, 5 uM NADPH and 100 uM alpha-KG.

The final reaction mixture contained 3.3% DMSO and inhibitors withconcentrations ranging 0.02-50 μM. The IDH1 enzyme was used at a finalconcentration of 0.25 nM. Following 45 minutes incubation, the reactionmixtures were quenched by the addition of 10 μL of 16% formic acidcontaining 800 nM of 5-carbon labeled ¹³C-2-HG). The protein was thenprecipitated by the addition of 2.5 volumes of acetonitrile followed bycentrifugation (3000×g, 20 minutes). The concentration of 2-HG in theresulting supernatants was measured by LC-MS (see below).

LC-MS method. Reaction mixture supernatants were submitted tochromatographic separation on a BiobasicAX column (2.1 mm×20 mm, 5 μmparticle, Thermo Scientific Inc.). The chromatographic mobile phaseswere A) 25 mM ammonium biocarbonate and B) acetonitrile (0.1% ammoniumhydroxide). Nicotinamide was eluted at 1 ml/min using a 85-5% B gradientover 0.9 minutes (Agilent 1200SL LC system, Thermofisher LX-4autosampler) and analyzed by multiple reaction monitoring (MRM) on aAPI4000 QTrap mass spectrometer (ABSciex, Framingham, Mass.) in thepositive electrospray ionization (ESI+) mode. The mass transition for2-HG and ¹³C-2-HG were 1474129 and 1524134, respectively. The relativeresponses (2-HG/¹³C-2-HG) were measured at varied inhibitorconcentrations and used to calculate inhibitory IC50 values (normalizedIC50 regression curves).

R132 Protein Expression and Purification.

IDH1 R132H was cloned into the pET47b vector using the restriction sitesXmal/Xhol which yields an in frame, N-terminal His₆ site cleavable withPrescission protease. This plasmid was transformed into Rosetta™ 2 (DE3)(Novagen) cells. In shake flasks, 8 L of cells were grown in TerrificBroth (Teknova) (plus kanamycin 50 μg/mL and chloramphenicol 34 μg/mL)at 37° C. to an OD₆₀₀ of 0.8 and protein expression was induced byaddition of IPTG to a concentration of 0.20 mM. The cells weresubsequently grown for 18 hours at 18° C.

(SEQ ID NO: 1) His₆-IDH1 (R132H) Uncut proteinMAHHHHHHSAALEVLFQGPGMSKKISGGSVVEMQGDEMTRIIWELIKEKLIFPYVELDLHSYDLGIENRDATNDQVTKDAAEAIKKHNVGVKCATITPDEKRVEEFKLKQMWKSPNGTIRNILGGTVFREAIICKNIPRLVSGWVKPIIIGHHAYGDQYRATDFVVPGPGKVEITYTPSDGTQKVTYLVHNFEEGGGVAMGMYNQDKSIEDFAHSSFQMALSKGWPLYLSTKNTILKKYDGRFKDIFQEIYDKQYKSQFEAQKIWYEHRLIDDMVAQAMKSEGGFIWACKNYDGDVQSDSVAQGYGSLGMMTSVLVCPDGKTVEAEAAHGTVTRHYRMYQKGQETSTNPIASIFAWTRGLAHRAKLDNNKELAFFANALEEVSIETIEAGFMTKDLAACIKGLPNVQRSDYLNTFEFMDKLGENLKIKLAQAKL (stop) (SEQ ID NO: 2)IDH1 (R132H) Prescission Cut Protein (N-term gpg is cloning artifact)GPGMSKKISGGSVVEMQGDEMTRIIWELIKEKLIFPYVELDLHSYDLGIENRDATNDQVTKDAAEAIKKHNVGVKCATITPDEKRVEEFKLKQMWKSPNGTIRNILGGTVFREAIICKNIPRLVSGWVKPIIIGHHAYGDQYRATDFVVPGPGKVEITYTPSDGTQKVTYLVHNFEEGGGVAMGMYNQDKSIEDFAHSSFQMALSKGWPLYLSTKNTILKKYDGRFKDIFQEIYDKQYKSQFEAQKIWYEHRLIDDMVAQAMKSEGGFIWACKNYDGDVQSDSVAQGYGSLGMMTSVLVCPDGKTVEAEAAHGTVTRHYRMYQKGQETSTNPIASIFAWTRGLAHRAKLDNNKELAFFANALEEVSIETIEAGFMTKDLAACIKGLPNVQRSDYLNTFEFMDKLGENLKIKLAQAKL (stop)

Purification

The cells were homogenized in Lysis Buffer with protease inhibitors(complete EDTA-free protease inhibitor tablets (Roche), 1 tablet per 50mL of buffer), DNAse, and to 200 μM PMSF and lysed in a Microfluidizer.After lysis, Triton X-100 was added to 0.1% and stirred at 4° C. for 30minutes.

The cleared lysate was loaded onto 2×5 mL HisTrap FF crude columns (GE),washed extensively with Lysis Buffer until the A₂₈₀ stabilized andeluted with Ni Elution Buffer. Peak eluted fractions were concentratedto 30 mL, EDTA was added to 1 mM and GST-Prescission protease was addedto 3 U/100 μg of protein. The sample was dialyzed against 2 L DialysisBuffer I (MWCO 50 kDa) for 6 hours at 4° C. then dialyzed against 2 L ofDialysis Buffer II for at least 6 more hours. GST-Prescission cleavedsample was rocked with Glutathione Agarose Beads, spun down and then thesupernatant was loaded through a 5 mL HisTrap HP column and the flowthrough was collected.

Flow through was then diluted with ice cold 20 mM Tris pH 7.4 and 1 mMTCEP until the conductivity dropped to less than 5 mS/cm (a roughlythree fold dilution). This sample was then flowed through a HiTrap Qcolumn and the flow through was concentrated to 10 mL and loaded onto anequilibrated 26/60 Superdex 200 column using SEC Buffer as the mobilephase. Peak fractions were collected, concentrated and aliquoted.

-   -   Lysis Buffer: 50 mM Tris pH=7.4, 500 mM NaCl, 20 mM Imidazole,        and 1 mM TCEP    -   Ni Elution Buffer: 50 mM Tris pH=7.4, 150 mM NaCl, 200 mM        Imidazole, and 1 mM TCEP    -   Dialysis Buffer I: 20 mM Tris pH=7.4, 150 mM NaCl, 1 mM TCEP,        and 50 mM Imidazole    -   Dialysis Buffer II: 20 mM Tris pH=7.4, 150 mM NaCl, and 1 mM        TCEP    -   SEC Buffer: 20 mM Tris pH=7.4, 150 mM NaCl, and 1 mM TCEP

The results of the mutant IDH1 biochemical assay (mIDH R132H) are givenin Table 30. Some of the examples were run in the assay multiple timesand therefore the IC₅₀ values are expressed as a range of activity.

Fluorescence Biochemical Assay

The IDH1 (R132H) mutant catalyzes the reduced form of NADP+ (NADPH) andα-ketoglutarate (α-KG) to form nicotinamide adenine dinucleotidephosphate (NADP+) and R (−)-2-hydroxyglutarate (2HG). The reaction canbe monitored kinetically by following the oxidation of NADPH to NADP+which is measured using fluorescence, excitation at 355 nm and emissionat 530 nm. Reactions were monitored using the Perkin-Elmer Envision,Model 2101. More specifically, the biochemical reactions were performedat room temperature in 384-well Greiner flat-bottom plates (Cat. No.781076) using a final reaction volume of 20 μL and the following assaybuffer conditions: 50 mM HEPES pH 7.5, 10 mM MgCl₂, 1 mM DTT, 0.02% BSA,0.02% Tween-20, 10 μM NADPH and 100 μM α-KG. The final reaction mixturecontained 2.5% DMSO and test compounds with concentrations ranging0.0000008-25 μM. The IDH1 (R132H) enzyme was used at a finalconcentration of 10 nM. Curve fitting for dose response IC50determinations was done in the Helios module of the software packageDAVID. The 4-parameter logistic model was used:y=min+((max−min)/1+(x/IC₅₀)^(slope))

TABLE 30 Results of the LC-MS and fluorescence biochemical assays. LC-MSFluorescence biochemical biochemical Example Number assay IC₅₀(μM) assayIC50 (μM) 1 0.084-0.236 2 >50 3 0.086-0.575 0.091-0.501 4 4.612 50.410-0.600 6 12.175 7 2.527 8 13.011 9 6.444 10 0.355-0.419 110.770-4.552 12 1.990-2.391 9.55 13 18.344-29.100 14 2.333-2.814 15 5.38316 >50 17 7.625 18 >50 19 >50 20 >50 21 4.169 22 19.671 23 0.502-0.59124 3.564 25 18.182−>50 26 >50 27 2.486-2.730 28 4.427-4.625 29 4.630-11.566 30 1.072 31 1.721 32 9.797 33 3.483 34 7.588 350.222-0.273 36 17.576 37 4.595 38 >50 39 8.806 40 20.34 41 0.291-0.58142 0.584 43 7.686 44 0.125 45 >50 46 0.234 47 7.481 48 2.090-2.601 1.9149 2.803 50 0.076-0.100 51 19.457 52 23.847 53 3.852 54 0.141 55 3.49456 9.502 57 1.393-3.153 7.58 58 >50 59 0.575 60 0.052 0.094 61 12.729 620.117-0.178 63 0.085-0.124 64 6.79 65 0.25 66 0.073 67 5.342 68 6.302 690.127-0.390 70 0.195-0.230 71 20.503 72 37.361 73 0.316 74 2.569 751.338 4.27 76 8.008 77 11.26 78 28.611 79 0.09 80 0.679 81 0.103 820.163-0.217 83 0.238-0.462 84 0.075 85 1.061 17.9 86 9.767 87 0.1260.245 88 0.148-0.344 89 0.203 0.308 90 0.272 0.275 91 2.875 920.211-0.544 0.598 93 0.405-0.905 94 4.487 95 0.655 0.571 96 >50 97 0.1950.166 98 0.628 99 0.184 100 0.169 101 2.382 102 0.401 103 3.184 1040.207 105 0.352 0.352 106 1.918 107 3.445 108 >50 109 0.542 0.939 1100.188 0.284 111 0.125 112 7.768 113 1.925 114 0.697 1.14 115 0.092 0.126116 2.038 117 0.163-0.217 118 1.302-2.152 119 0.117 0.149 1200.258-0.847 121 0.081-0.448 122 0.157-0.379 123 0.112 0.162 1240.081-0.298 0.791 125 1.012 126 0.118 127 0.158 0.215 128 0.565 1290.467 130 0.549-0.615 131 14.319 132 31.016 133 7.115 134 3.102 135 11.6136 6.455 137 3.14 138 1.061 139 1.252 2.5 140 0.089 0.114-0.181 1410.095 142 0.390-0.512 143 >50 144 >50 145 6.807 146 11.362 147 6.445 1483.544 149 0.647 150 0.53 0.538 151 1.363 152 0.385 0.598 153 0.759 0.582154 0.049 0.091 155 0.04 156 0.232 0.248 157 >50 158 0.873 1.41 1590.287 160 6.078 161 6.502 162 0.009-0.035 0.020-0.043 163 0.149 1640.067 0.0339 165 0.183 0.143 166 0.637 1.56 167 0.254 168 0.102 1690.195 170 1.083 171 6.161 172 0.245-0.274 173 2.908 174 0.056-0.1180.283 175 8.156 176 0.125 0.138 177 4.333 178 0.097 0.0687 179 5.973 1800.194 181 10.232 182 0.309-0.370 183 36.818 184 0.696 185 6.066 186 0.04187 3.899 188 0.089 0.17 189 0.117 190 2.134 191 6.969 192 0.221 0.294193 0.097 194 4.333 195 5.748 196 0.083 197 15.05 198 0.173 0.179 1992.435 200 0.08 0.0665 201 0.927 202 0.025 0.0541 203 1.856 204 0.0620.0955 205 0.199 0.219 206 1.458 0.81 207 0.069 0.0169 208 0.0850.108-0.183 209 0.088 0.0881 210 0.576 0.343 211 0.439 212 0.132 0.024213 2.913 214 0.298 0.791 215 0.390 0.419 216 0.031 0.0206 2170.177-0.206 0.079-0.146 218 1.373 0.625 219 0.613 220 0.529 0.247 2210.098 0.0476 222 0.505 0.296 223 0.293 0.14 224 <0.022 0.0166 225 0.0260.0173 226 0.114 0.0832 227 0.065 0.0339 228 0.067 0.0463 229 0.1130.0662 230 0.072 0.0415 231 0.327 0.242 232 0.251 0.755 233 0.147 0.0684234 >50 >25 235 0.039 0.0141 236 0.372 0.338 237 0.877 0.219 238 9.8 2390.038 0.073 240 0.030 0.0506 241 0.155 0.213 242 0.048 0.242 2430.260-0.914 1.21-1.6  244 0.863 0.774 245 0.184 0.103 246 0.497-0.5890.236-0.316 247 1.373 1.79 248 0.687 0.842 249 0.585 0.616 250 0.0310.0468 251 0.064 0.0878 252 0.033 0.0608 253 0.559 254 0.656 1.12 25510.369 256 0.197 257 0.242-0.282 0.221-0.27  258 0.378 259 2.569 2600.186 261 0.040 0.0639 262 0.058 0.0991 263 0.679 264 0.108 265 <0.0220.0232 266 0.152 267 3.308 268 20.567 269 0.467 270 0.463 271 0.1000.108 272 1.717 2.28 273 0.202 0.143 274 0.104 0.0524 275 0.261 0.273276 0.298 0.175 277 0.094 0.0899 278 0.241 0.29 279 0.312 280 7.823 281<0.022 282 0.180 283 0.538 0.635 284 2.023 1.38 285 0.390 0.375 2861.807 2.54 287 34.794 >25 288 0.053 0.269 289 0.316 0.19 290 2.2220.414-0.975 291 4.64 292 0.049 0.0645 293 2.696 294 0.095 0.648 2950.342 0.252 296 0.085 297 0.848 298 0.188 1.04 299 4.052 10.4 300 1.6391.84 301 0.0887 302 0.131 303 0.326 304 2.107 305 0.065 0.0413 306 4.04312.5 307 0.225 308 0.259 0.703 309 0.868 1.66 310 36.281 >25 311 4.139312 0.051 0.024 313 0.073 0.0799 314 1.311 1.59 315 5.916 316 0.131 3170.050 318 5.007 319 0.705 320 2.410 321 1.214 322 0.026 0.0666 323 17.1324 0.483 325 15.718 18.5-21.4 326 0.115 0.268-0.369 327 19.2 3280.329-1.144 0.558-0.843 329 2.164 5.62 330 0.026 0.0545 331 6.083 7.65332 0.052-0.072 0.0693 333 0.128 0.335 334 0.646 335 6.53 336 0.236 3377.22 338 0.148 0.145 339 3.101 4.4 340 <0.022 0.0276 341 2.13 342 0.0290.0278 343 4.08 344 0.265 345 >50 346 32.256 347 >50 348 >50 349 4.01024.2 350 0.583 0.731 351 >50 352 >50 353 >50 354 >50 355 33.589 >25 3561.642 4.53 357 13.229 358 0.864 1.53 359 >50 >25 360 3.035 4.37-11.9 3610.781 0.736 362 0.063 0.0621 363 14.441 23.3 364 0.964 1.06 365 >50 >25366 2.602 20.2-21.7 367 20.809 >25 368 0.706 0.862 369 >50 >25 370 6.6493.01 371 25.036 >25 372 4.19 373 39.696 >25 374 1.617 1.89-2.42375 >50 >25 376 2.321 3.27-4.33 377 >25 378 4.19 379 >25 380 0.839 38120 382 0.203 0.349 383 5.16 384 0.068 0.107 385 22.5 386 4.74 387 20.6388 4.37 389 1.83 390 0.140 0.213 391 2.35-5.33 392 0.694 0.355-0.697393 12.1 394 0.268 0.34 395 9.36 396 0.189 0.224 397 7.14 3980.094-0.123 0.189 399 >25 400 0.648 401 19 402 0.362 0.39 403 >25 4040.964 405 21.1 406 1.82 407 6.39 408 0.237 0.349 409 1.35 4100.340-0.440 0.098-0.521 411 2.907 412 0.190 413 21.616 414 6.026-7.6755.47-8.32 415 26.674 416 1.592 417 20.287 418 0.808 419 2.833 420 >50421 27.999 >25 422 2.136 3.81 423 7.595 14.8 424 0.162 0.491-0.747 4250.909 2.45 426 <0.022-0.038  0.019-0.058 427 1.229 2.09 428 >50 >25 4296.407 9.78 430 0.133 0.0908 431 0.568 0.811 432 0.040 0.0448 433 6.6755.31 434 0.153 2.19-3.96 435 >25 436 0.291 0.364-0.373 437 2.69-3.18438 >25 439 6.155 440 0.125 0.105-0.122 441 4.229 1.63-10.6 442 0.1360.225 443 0.063-0.077 0.0414 444 0.040 0.0266 445 2.526 2.46 4460.079-0.081 0.039 447 3.876 448 0.034 0.0373 449 5.43 450 0.062 0.0518451 0.207 0.386 452 0.063-0.065 0.134 453 11.400 14.5 454 0.401 0.601455 6.218 >25 456 0.082 0.041 457 <0.022 0.013 458 0.069 0.0588 4590.991 1.16 460 461 2.275 462 1.924 2.87 463 >50 464 <0.022 0.020-0.055465 0.164 466 0.665 0.821 467 9.82 468 3.03-11.8 469 0.077 0.185-0.198470 0.075 0.172 471 0.925 0.78 472 14.8 473 0.0986 474 7.1 475 0.3410.355 476 >50 477 >50 478 >50 479 >50 480 >50 481 0.780 2.52 482 >50 >25483 0.096 0.202 484 5.160 21.3 485 2.12 486 0.873 487 1 488 0.311 0.437489 4.15 490 2.61 491 0.821 492 0.249 493 0.067 0.139 494 1.649 0.595495 0.712 0.734 496 0.751 0.723 497 1.13 498 5.27 499 2.39 500 1.45 5010.494 502 0.305 503 0.546 0.96 504 0.268 0.243 505 0.275 506 0.46 5070.0773 508 0.553 0.484 509 0.553 0.484 510 0.0294 511 0.062 512 0.4500.38 513 0.0336 514 515 0.0287 516 0.082 0.0592 517 1.58 518 0.0785 5190.123 0.363 520 0.080 0.053-0.321 521 0.23 522 0.745 523 0.165 524 0.0260.0211 525 0.085 0.108-0.183 526 0.088 0.0427 527 0.0851 528 0.0770.0613 529 0.117 0.0622 530 <0.022 0.00835 531 0.00812 532 0.0727 5330.307 0.227 534 0.188 0.331 535 0.183 536 0.104 537 0.400 0.257 5380.416 0.268 539 2.66 540 0.878 0.573 541 0.266 0.0899 542 0.090 0.0877543 >25 544 0.075 0.0477 545 0.0943 546 0.059 0.0423 547 0.158 0.146 5480.184 549 1.840 550 0.791 0.276 552 <0.022 0.0199 553 0.521 0.41 5540.075 0.217 555 <0.022 556 <0.072 557 0.246 0.237 558 0.283 559 17.6 56025 561 0.552 562 0.364 563 0.04 564 0.0501 565 0.309 566 0.135 0.13 5675.41 568 0.086-0.141 0.067-0.161 569 0.0575 570 0.0446 571 0.0742 5720.0781 573 0.00786 574 0.204 0.324 575 1.91 576 2.37 577 1.65 578 1.07579 0.911 0.591 580 0.153 0.193 581 0.260 0.432 582 0.204 583 >25 58410.6 585 6.7 586 2.797 1.02 587 1.95 588 0.764 0.85 589 2.92 590 <0.0220.006-0.009 591 <0.022 0.018 592 0.138 0.077 593 0.077 0.036 594 0.2570.178 595 0.121 0.053 596 0.161 0.154 597 0.457 0.741 598 0.519 0.715599 0.155 0.265 600 0.488 0.729 601 0.042 0.042 602 0.049 0.034 6030.244 0.336 604 0.112 0.161

IDH Cellular Assay

The IDH cellular assay consists of two side-by-side comparatorassays: 1) 2HG oncometabolite detection assay using LC-MS (See MutantIDH1 biochemical assay for LC-MS detection details) and 2) Cellproliferation assay to monitor off-target killing of cells and tonormalize 2HG level change. IDH1 cellular screens were run with theHCT-116 cell line (express endogenous level of IDH1mut R132H, availablefrom Horizon Discoveries X-Man isogenic human cell lines, catalog #HD104-013). The cells were grown in DMEM (LONZA Cat#12-540F) with 10%Fetal bovine serum (Gibco cat #10099) and 1× non-essential amino acids(NEAA LONZA cat #13-114E). Panel assays were run periodically to testcompound activity in cell lines with different endogenousmutations—HT1080 (IDH1mut R132C, EMEM+10% FBS), SNU-1079 (IDH1mut R132C,RPMI+10% FBS+1% sodium pyruvate), and SW1353 (IDH2mut R172S, RPMI+10%FBS+1% sodium pyruvate).

The assay process is as follows:

Day 1: cells were seeded in 384-well plates (Corning Cat#3707) intriplicates for both the cell proliferation and 2HG assay, and incubatedat 37 C, 95% Rh, 5% CO2 overnight.Day 2: compounds were serially diluted 1:3 (10 point dilution from 10 mMsolutions in DMSO) and delivered to the cell assay plates via acousticdispenser, with final concentration ranging from 30 uM to 1.5 nM. Theplates were returned to the incubator after treatment and incubated for48 hours.Day 4 Proliferation assay: CTG (cell titer-glo, Promega part # G755B)was added to the assay plates and luminescence signal was read on theplate reader.Day 4 2HG assay: Extraction sample preparation consisted of aspiratingall media from the assay plates, adding 70 ul of 90% methanol in water,dry ice incubation for 15 minutes, centrifuging at 2000 rpm for 30 minto ensure all particulates have settled, and transferring 30 ul of thesupernatant into LC-MS ready plates. LC-MS analysis follows.

Certain compounds of the invention have been tested in the IDH CellularAssay.

What is claimed is:
 1. A compound of formula (I)

wherein: R¹ and R² are each independently hydrogen, deuterium, halo,hydroxyl, NH₂, aryl, heteroaryl, or optionally substituted C₁₋₄ alkyl,wherein said C₁₋₄ alkyl is optionally substituted with one to threesubstituents each independently selected from the group consisting of:halo, hydroxyl, and NH₂; R^(3a) is hydrogen, deuterium, C₁₋₆ alkyl,phenyl, or benzyl and R^(3b) is hydrogen, deuterium, or C₁₋₆ alkyl; orR^(3a) and R^(3b) are joined together forming an optionally substituted3-7 membered cycloalkyl ring or an optionally substituted 4-7 memberedheterocyclic ring, wherein said cycloalkyl and heterocyclic rings areeach optionally substituted with one or two substituents eachindependently selected from the group consisting of: halo, hydroxyl,oxo, NH₂, and C₁₋₃ alkyl; R^(4a) is hydrogen, C₁₋₆ alkyl, optionallysubstituted phenyl, optionally substituted benzyl, optionallysubstituted heteroaryl, or methylene-dibenzene, wherein said phenyl,benzyl, and heteroaryl rings are optionally substituted with one tothree substituents each independently selected from the group consistingof: halo, hydroxyl, cyano, nitro, C₁₋₄ alkoxy, C₁₋₃ haloalkyl, C₁₋₃haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 5-6 membered heterocyclic, phenoxy, —COOR^(b), —SO₂R^(b),—NHC(O)R^(b), and —NR^(b)R^(b) and R^(4b) is hydrogen, deuterium, orC₁₋₃ alkyl; or R^(4a) and R^(4b) are joined together forming anoptionally substituted 3-7 membered cycloalkyl ring or an optionallysubstituted 4-7 membered heterocyclic ring, wherein said cycloalkyl andheterocyclic rings are optionally substituted with one or twosubstituents each independently selected from the group consisting of:halo, hydroxyl, oxo, NH₂, and C₁₋₃ alkyl, provided that only one ofR^(3a) and R^(3b) and R^(4a) and R^(4b) are joined together forming aring; R^(5a) is hydrogen or deuterium; R^(5b) is hydrogen, deuterium,methyl, ethyl, CD₃, CF₃, CH₂F, or CHF₂ and R⁶ is optionally substitutedC₁₋₆ alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclic, or optionallysubstituted C₃₋₁₀ cycloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with one substituent selected from the group consisting ofhydroxyl, C₁₋₃ alkoxy and —OR^(a), wherein said aryl, heteroaryl,heterocyclic and C₃₋₁₀ cycloalkyl are optionally substituted with one tothree substituents each independently selected from the group consistingof: halo; hydroxyl; cyano; nitro; C₁₋₄ alkoxy; C₁₋₃ haloalkyl; C₁₋₃haloalkoxy; C₁₋₆ alkyl; C₃₋₆ cycloalkyl optionally substituted with oneto three substituents each independently selected from the groupconsisting of: hydroxyl, cyano, C₁₋₃ alkyl, C₁₋₃ alkoxy, and C₁₋₃haloalkyl; phenyl optionally substituted with one to three substituentseach independently selected from the group consisting of: halo,hydroxyl, cyano, nitro, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 5-6 memberedheterocyclic, phenoxy, —COOR^(b), —SO₂R^(b), —NHC(O)R^(b), andNR^(b)R^(b); 5-6 membered heteroaryl optionally substituted with one tothree substituents each independently selected from the group consistingof: halo, hydroxyl, cyano, C₁₋₃ alkyl, C₁₋₃ alkoxy; 5-6 memberedheterocyclic optionally substituted with one to three substituents eachindependently selected from the group consisting of: halo, hydroxyl,oxo, NH₂, and C₁₋₃ alkyl; —CH₂R^(a); —OR^(a); —C(O)R^(a); —NR^(a)R^(b);—COOR^(a); —SO₂R^(a); —SO₂R^(b); —NHC(O)R^(a); —NHC(O)R^(b);—C(O)NR^(a)R^(b); —C(O)NHR^(b); and —SO₂NR^(b)R^(b); or R^(5b) and R⁶are joined together forming an optionally substituted C₃₋₇ cycloalkylgroup or an optionally substituted group of formula (a):

wherein n is 1, 2, or 3 and said C₃₋₇ cycloalkyl and group of formula(a) are optionally substituted with one to three substituents eachindependently selected from the group consisting of: halo, hydroxyl,cyano, nitro, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic,benzyloxy, —COOR^(b), —SO₂R^(b), —NHC(O)R^(b), and —NR^(b)R^(b); eachR^(a) is independently optionally substituted phenyl, optionallysubstituted heteroaryl, optionally substituted heterocyclic, oroptionally substituted C₃₋₇ cycloalkyl, wherein said phenyl andheteroaryl are optionally substituted with one to three substituentseach independently selected from the group consisting of halo, hydroxyl,cyano, nitro, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, and C₁₋₃alkyl, wherein said heterocyclic is optionally substituted with one tothree substituents each independently selected from the group consistingof halo, hydroxyl, oxo, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy,C₁₋₄ alkyl, C₃₋₅ cycloalkyl, —C(O)R^(b), and —NR^(b)R^(b), and whereinsaid C₃₋₇ cycloalkyl is optionally substituted with one to threesubstituents each independently selected from the group consisting ofhalo, hydroxyl, oxo, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, andC₁₋₃ alkyl; and each R^(b) is independently hydrogen or C₁₋₆ alkyl; or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1 of the formula (III)

or a pharmaceutically acceptable salt thereof.
 3. The compound accordingto claim 2 of the formula (IV)

or a pharmaceutically acceptable salt thereof.
 4. The compound accordingto claim 3 wherein R^(3a) and R^(3b) are both hydrogen; or apharmaceutically acceptable salt thereof.
 5. The compound according toclaim 4 wherein R^(5a) is hydrogen and R^(5b) is hydrogen, methyl,ethyl, or CF₃; or a pharmaceutically acceptable salt thereof.
 6. Thecompound according to claim 5 wherein R^(5b) is methyl; or apharmaceutically acceptable salt thereof.
 7. The compound according toclaim 6 wherein R¹ is hydrogen, fluoro or chloro and R² is hydrogen,fluoro, chloro, or methyl; or a pharmaceutically acceptable saltthereof.
 8. The compound according to claim 7 wherein R¹ and R² are bothhydrogen; or a pharmaceutically acceptable salt thereof.
 9. The compoundaccording to claim 8 wherein R^(4a) is hydrogen, C₁₋₆ alkyl, optionallysubstituted phenyl, optionally substituted benzyl, optionallysubstituted heteroaryl, or methylene-dibenzene, wherein said phenyl,benzyl, and heteroaryl rings are optionally substituted with one tothree substituents each independently selected from the group consistingof: halo, hydroxyl, cyano, nitro, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 5-6membered heterocyclic, phenoxy, —COOR^(b), —SO₂R^(b), —NHC(O)R^(b), and—NR^(b)R^(b) and R^(4b) is hydrogen or C₁₋₃ alkyl; or a pharmaceuticallyacceptable salt thereof.
 10. The compound according to claim 9 whereinR^(4b) is hydrogen or methyl; or a pharmaceutically acceptable saltthereof.
 11. The compound according claim 10 wherein R^(4b) is hydrogen;or a pharmaceutically acceptable salt thereof.
 12. The compoundaccording to claim 11 R^(4a) is hydrogen, methyl, ethyl, isopropyl,phenyl, 4-fluorophenyl, 4-methoxyphenyl, biphenyl, benzyl, or pyridinyl;or a pharmaceutically acceptable salt thereof.
 13. The compoundaccording to claim 12 wherein R^(4a) is isopropyl; or a pharmaceuticallyacceptable salt thereof.
 14. The compound according to claim 1 whereinR⁶ is methyl, C₅₋₁₀ cycloalkyl, optionally substituted phenyl,optionally substituted pyridinyl, optionally substituted pyrimidinyl,optionally substituted pyridazinyl, optionally substituted pyrazinyl,optionally substituted triazolyl, optionally substituted pyrazolyl,optionally substituted thiazolyl, optionally substituted1,3,4-oxadiazolyl, optionally substituted 1,2,4-oxadiazolyl, optionallysubstituted isoxazolyl, thienyl, oxazolyl, quinolinyl, optionallysubstituted benzimidazolyl, benzthiazolyl, benzoxazolyl,tetrazolo[1,5-a]pyridinyl, imidazo[2,1-b][1,3,4]thiadiazolyl, optionallysubstituted piperidinyl, optionally substituted piperazinyl,tetrahydrofuranyl, tetrahydropyranyl, optionally substitutedtetrahydro-thiopyran1,1-dioxide, 1H-pyrrolo[2,3-b]pyridinyl,2,3-dihydro-benzo[1,4]dioxinyl,5,6,7,8-tetrahydro-[1,2,4]trazolo[4,3-a]pyrazinyl,4,5,6,7-tetrahydro-benzothiazolyl, indolizinyl, cyclopropyl,cyclopentyl, or cyclohexyl, wherein said phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazolyl, pyrazolyl, thiazolyl,1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, isoxazolyl, benzimidazolyl,piperidinyl, piperazinyl, and tetrahydro-thiopyran1,1-dioxide are eachoptionally substituted with one or two substituents as defined informula (I).
 15. The compound according to claim 14 wherein R⁶ isoptionally substituted with one or two substituents each independentlyselected from the group consisting of: halo; hydroxy; nitro; C₁₋₄alkoxy; C₁₋₃ haloalkyl; C₁₋₃ haloalkoxy; C₁₋₆ alkyl; C₃₋₆ cycloalkyloptionally substituted with one substituent selected from the groupconsisting of: cyano, C₁₋₃ alkyl, and C₁₋₃ alkoxy; phenyl optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of: fluoro, chloro, methyl, cyano, andmethoxy; and 5-6 membered heteroaryl optionally substituted with one ortwo methyl groups; or a pharmaceutically acceptable salt thereof. 16.The compound according to claim 15 wherein R⁶ is optionally substituted1,3,4-oxadiazolyl or optionally substituted 1,2,4-oxadiazolyl; or apharmaceutically acceptable salt thereof.
 17. The compound according toclaim 14 wherein R⁶ is substituted with one —CH₂R^(a), —C(O)R^(a),—NHC(O)R^(a), —NHC(O)R^(b), —C(O)NHR^(a), C(O)NHR^(b), —OR^(a),—NR^(a)R^(b), —SO₂NR^(b)R^(b), —SO₂R^(a), or —SO₂R^(b) group; or apharmaceutically acceptable salt thereof.
 18. The compound according toclaim 17 wherein R^(a) is (a) phenyl optionally substituted with one ortwo substituents each independently selected from the group consistingof fluoro, chloro and bromo; (b) optionally substituted 5-6 memberedheteroaryl; (c) C₅₋₇ cycloalkyl optionally substituted with one or twosubstituents each independently selected from the group consisting offluoro, hydroxy, methyl, and C₁₋₃ haloalkoxy; or (d) a heterocyclicgroup selected from the group consisting of: piperidinyl, piperazinyl,morpholinyl, tetrahydropyranyl, tetrahydro-thiopyran1,1-dioxide,1,4-diazepanyl, 4,7-diaza-spiro[2.5]octanyl,3,8-diaza-bicyclo[3.2.1]octanyl, 3,8-diaza-bicyclo[4.2.0]octanyl,octahydro-pyrrolo[1,2-a]pyrazinyl, octahydro-pyrido[1,2-a]pyrazinyl,octahydro-pyrrolo[3,4-c]pyrrolyl, and5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazinyl each of which is optionallysubstituted with one to three substituents each independently selectedfrom the group consisting of: hydroxy, fluoro, amino, dimethylamino,C₁₋₃ haloalkoxy, C₁₋₃ alkyl, and C₃₋₅ cycloalkyl; or a pharmaceuticallyacceptable salt thereof.
 19. The compound according to claim 18 whereinR⁶ is optionally substituted phenyl; or a pharmaceutically acceptablesalt thereof.
 20. The compound according to claim 19 wherein the phenylis substituted with one CH₂R^(a), —C(O)R^(a), or —C(O)NHR^(a) group inthe para position; or a pharmaceutically acceptable salt thereof. 21.The compound according to claim 2 of the formula (V)

wherein R^(4a) is phenyl and R^(4b) is hydrogen; or a pharmaceuticallyacceptable salt there
 22. The compound according to claim 1 selectedfrom the group consisting of:(S)-4-isopropy-3-(2-(((S)-1-(4-(2-yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;N-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)phenyl)cyclohexanecarboxamide;(S)-3-(2-(((S)-1-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-4-isopropyl-3-(2-(((S)-1-(4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;2-fluoro-N-(4-hydroxy-4-methylcyclohexyl)-4-((S)-1-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)benzamide;(S)-3-(2-((S)-1-(4-((4-amino-4-methylpiperidin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-((S)-1-(4-((4-(dimethylamino)piperidin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-4-isopropyl-3-(2-((S)-1-(4-((4-methylpiperazin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;(S)-4-isopropyl-4-methyl-3-(2-((S)-1-(4-((4-methylpiperazin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;(S)-4-isopropyl-3-(2-((S)-1-(6-phenylpyridin-3-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;(S)-3-(2-((S)-1-(4-benzoylphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-4-isopropyl-3-(2-(((S)-1-(5-phenyl-1,3,4-thiadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;(4S)-4-isopropyl-3-(2-(1-(5-phenylpyrimidin-2-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;3-(5-fluoro-2-((1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;(S)-4-isopropyl-3-(2-(((S)-1-(1-(3-methoxyphenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;(S)-3-(2-(((S)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-4-isopropyl-3-(2-(((S)-1-(3-(m-tolyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;(S)-3-(2-(((S)-1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-((S)-1-(5-(4-fluoro-2-methylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-4-Isopropyl-3-{2-[(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amino]-pyrimidin-4-yl}-oxazolidin-2-one;(S)-4-isopropyl-3-(2-((S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;(S)-3-(2-((S)-1-(2-fluoro-4-isopropylphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-((S)-1-(4-isobutoxy-3-methylphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-(((S)-1-(4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(5-fluoro-2-(((S)-1-(4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;2-fluoro-N-(trans-4-hydroxycyclohexyl)-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide;(S)-3-(5-fluoro-2-((S)-1-(3-fluoro-4-(piperidine-1-carbonyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;N-cyclohexyl-2-fluoro-4-((S)-1-(5-fluoro-4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide;N-cyclohexyl-2-fluoro-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide;and(S)-3-(5-fluoro-2-((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;or a pharmaceutically acceptable salt thereof.
 23. The compoundaccording to claim 1 selected from the group consisting of:(S)-3-(2-(((S)-1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-(((S)-1-(4-((4,4-difluoropiperidin-1-yl)methyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(5-fluoro-2-(1-(4-phenoxyphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;(S)-3-(2-((S)-1-(4-(4-fluorophenoxy)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-((S)-1-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-(((S)-1-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-((S)-1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-((S)-1-(5-(4-fluorophenoxy)pyrazin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-4-isopropyl-3-(2-((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;and(S)-3-(2-((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;or a pharmaceutically acceptable salt thereof.
 24. The compoundaccording to claim 1 selected from the group consisting of:(S)-3-(2-(1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-5-fluoropyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one;(S)-3-(6-chloro-2-(1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one;(S)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;2-chloro-N-cyclopentyl-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide;(S)-3-(2-((S)-1-(4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-((S)-1-(4-(4,7-diazaspiro[2.5]octan-4-ylmethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-((S)-1-(4-((4-acetylpiperazin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(2-(((S)-1-(4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;(S)-3-(5-fluoro-2-(((S)-1-(4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one;and2-fluoro-N-(trans-4-hydroxycyclohexyl)-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide;or a pharmaceutically acceptable salt thereof.
 25. The compoundaccording to claim 1 wherein each R¹ and R² is independently hydrogen,deuterium, halo, hydroxyl, NH₂, aryl, heteroaryl, or optionallysubstituted C₁₋₄ alkyl, wherein said C₁₋₄ alkyl is optionallysubstituted with one to three substituents each independently selectedfrom the group consisting of: halo, hydroxyl, and NH₂; R^(3a) ishydrogen, deuterium, C₁₋₆ alkyl, phenyl, or benzyl and R^(3b) ishydrogen, deuterium, or C₁₋₆ alkyl; or R^(3a) and R^(3b) are joinedtogether forming an optionally substituted 3-7 membered cycloalkyl ringor an optionally substituted 4-7 membered heterocyclic ring, whereinsaid cycloalkyl and heterocyclic rings are each optionally substitutedwith one or two substituents each independently selected from the groupconsisting of: halo, hydroxyl, oxo, NH₂, and C₁₋₃ alkyl; R^(4a) ishydrogen, C₁₋₆ alkyl, optionally substituted phenyl, optionallysubstituted benzyl, optionally substituted heteroaryl, ormethylene-dibenzene, wherein said phenyl, benzyl, and heteroaryl ringsare optionally substituted with one to three substituents eachindependently selected from the group consisting of: halo, hydroxyl,cyano, nitro, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic,phenoxy, COOR^(b), SO₂R^(b), NHC(O)R^(b), and NR^(b)R^(b) and R^(4b) ishydrogen, deuterium, or C₁₋₃ alkyl; or R^(4a) and R^(4b) are joinedtogether forming an optionally substituted 3-7 membered cycloalkyl ringor an optionally substituted 4-7 membered heterocyclic ring, whereinsaid cycloalkyl and heterocyclic rings are optionally substituted withone or two substituents each independently selected from the groupconsisting of: halo, hydroxyl, oxo, NH₂, and C₁₋₃ alkyl, provided thatonly one of R^(3a) and R^(3b) and R^(4a) and R^(4b) are joined togetherforming a ring; R^(5a) is hydrogen or deuterium; R^(5b) is hydrogen,deuterium, methyl, ethyl, CD₃, CF₃, CH₂F, or CHF₂ and R⁶ is optionallysubstituted C₁₋₆ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclic, oroptionally substituted C₅₋₁₀ cycloalkyl, wherein said C₁₋₆ alkyl isoptionally substituted with one substituent selected from the groupconsisting of hydroxyl, C₁₋₃ alkoxy and —OR^(a); wherein said aryl,heteroaryl, heterocyclic and C₅₋₁₀ cycloalkyl are optionally substitutedwith one to three substituents each independently selected from thegroup consisting of: halo; hydroxyl; cyano; nitro; C₁₋₃ alkoxy; C₁₋₃haloalkyl; C₁₋₃ haloalkoxy; C₁₋₆ alkyl; C₃₋₆ cycloalkyl; phenyloptionally substituted with one to three substituents each independentlyselected from the group consisting of: halo, hydroxyl, cyano, nitro,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₁₋₆ alkyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy,COOR^(b), SO₂R^(b), NHC(O)R^(b), and NR^(b)R^(b); 5-6 memberedheteroaryl; 5-6 membered heterocyclic optionally substituted with one tothree substituents each independently selected from the group consistingof: halo, hydroxyl, oxo, NH₂, and C₁₋₃ alkyl; —CH₂R^(a); —OR^(a);—C(O)R^(a); —NR^(a)R^(b); —COOR^(a); —SO₂R^(a); NHC(O)R^(a); and—SO₂NR^(b)R^(b); or R^(5b) and R⁶ are joined together forming anoptionally substituted C₃₋₇ cycloalkyl group or an optionallysubstituted group of formula (a):

wherein n is 1, 2, or 3 and said C₃₋₇ cycloalkyl and group of formula(a) are optionally substituted with one to three substituents eachindependently selected from the group consisting of: halo, hydroxyl,cyano, nitro, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic,benzyloxy, COOR^(b), SO₂R^(b), NHC(O)R^(b), and NR^(b)R^(b); each R^(a)is independently optionally substituted phenyl, optionally substitutedheteroaryl, or optionally substituted 4-7 membered heterocyclic, whereinsaid phenyl and heteroaryl are optionally substituted with one to threesubstituents each independently selected from the group consisting ofhalo, hydroxyl, cyano, nitro, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃haloalkoxy, and C₁₋₃ alkyl, wherein said 4-7 membered heterocyclic isoptionally substituted with one to three substituents each independentlyselected from the group consisting of halo, hydroxyl, oxo, C₁₋₃ alkoxy,C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, and C₁₋₃ alkyl; and each R^(b) isindependently hydrogen or C₁₋₆ alkyl; or a pharmaceutically acceptablesalt thereof.
 26. The compound according to claim 25 wherein R¹ ishydrogen, fluoro, chloro, or methyl; R² is hydrogen; R^(3a) is hydrogen,methyl, or phenyl; R^(3b) is hydrogen or methyl; R^(4a) is hydrogen,C₁₋₄ alkyl, optionally substituted phenyl, optionally substitutedbenzyl, optionally substituted heteroaryl, or methylene-dibenzene;R^(4b) is hydrogen or methyl; R^(5a) is H; and R^(5b) is hydrogen,methyl, ethyl, or CF₃; or a pharmaceutically acceptable salt thereof.27. The compound according to claim 26 wherein R⁶ is isopropyl,optionally substituted aryl, optionally substituted pyrazolyl,optionally substituted pyridinyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzo[b][1,4]dioxinyl, or optionally substituted C₅₋₁₀cycloalkyl; or a pharmaceutically acceptable salt thereof.
 28. Apharmaceutical composition comprising a compound according to claim 1,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 29. A method for the treatment of adisease or disorder associated with a mutant IDH protein having aneomorphic activity comprising administration of a therapeuticallyeffective amount of a compound according to claim 1, or apharmaceutically acceptable salt thereof, to subject in need of thereof.30. A method for the treatment of a disease or disorder associated witha mutant IDH protein having a neomorphic activity comprisingadministration of a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, andanother therapeutic agent to subject in need of thereof.